COMPOSITIONS AND METHODS FOR MEDIATING EPS.

Abstract

This disclosure relates to methods for inhibiting biofilm stability comprising contacting the biofilm with an effective amount of an agent that interferes with the binding of a polyamine to DNA in the biofilm. Methods for treating a biofilm in a subject are also provided herein, comprising administering to the biofilm-infected subject an effective amount of an agent that interferes with the binding of a polyamine to DNA in the biofilm. Methods for treating a biofilm in a patient with systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF) are further described herein, comprising administering an effective amount of an agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment.

Description

COMPOSITIONS AND METHODS FOR MEDIATING EPS TECHNICAL FIELD OF THE INVENTION The present disclosure relates generally to methods and compositions for removing or inhibiting bacterial extracellular polymeric substance (EPS). BACKGROUND OF THE INVENTION Biofilms play an important role in medical, agricultural, and industrial settings. Biofilms are responsible for a significant part of diseases, both animal and plant, as well as for the fouling of industrial equipment and, as such, are the focus of an intense research effort. Eradication or treatment of biofilms is particularly difficult to achieve due to multiple factors, including production of an extracellular matrix that forms a physical barrier to antimicrobial effectors, altered physiology that is less susceptible to environmental stressors, and cooperative interactions between biofilm constituents. The biofilm matrix is ​​variably composed of polysaccharides, proteins, and, perhaps universally, extracellular DNA (eDNA). The eDNA of a microbial biofilm is a critical component of the extracellular matrix that provides protection. Weakening of the biofilm's eDNA structure, through DNA degradation or removal of the DNA-binding proteins that stabilize the structure, results in a catastrophic collapse of the biofilm and the release of the resident bacterium into the biofilm. a more vulnerable state. Bacteria are found in nature in two different states; planktonic bacteria are free-living, while bacteria that develop in a communal architecture are called biofilms (either on a surface or as aggregates). The CDC and NIH estimate that approximately 80% of all bacterial infections involve a necessary biofilm state. Dongari-Bagtzoglou et al. (2008) Expert Rev Anti Infect Ther. 6(2):201-8. These include otitis media (OM), chronic rhinosinusitis (CRS), chronic lung infections, chronic wound infections, periodontitis, cystitis, and infections of medical implants and indwelling catheters, among many others. In fact, one of the most common reasons for seeking pediatric medical attention is OM [caused by non-typable Haemphilus influenzae (NTHI) Streptococcus pneumoniae, Moraxella catarrhalis] and in adults, cystitis [eg, uropathogenic E. coli (UPEC) ]; consequently, antibiotic prescriptions are the most common for these complaints. In the United States, an estimated 500,000 deaths a year are attributed to the direct consequences of bacterial biofilm infections. The economic impacts are staggering [$25 billion (billion) for chronic wounds, $14 billion for periodontitis, $5 billion for OM and $1 billion for cystitis]. The global prevalence of diseases mediated by Rcncpn / Lznza / YiAi biofilms, the increasing rate of antibiotic-resistant bacterial infections, particularly among high-priority ESKAPE pathogens (Enterobacter spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterococcus faecium financial), and bioburden create a critical need to develop novel approaches to treat recalcitrant infections caused by organized bacterial communities. Therefore, there is a need to break the protective barrier of biofilms to treat or kill associated bacterial infections and remove them from surfaces and from water systems. BRIEF DESCRIPTION OF THE INVENTION The self-produced extracellular matrix (or extracellular polymeric substance, EPS) that protects bacteria residing within biofilms from immune kill and antimicrobials is essential for pathogenic biofilms to cause chronic and recurrent infections, as biofilms serve as a recalcitrant reservoir of these disease-causing bacteria. EPS constituents are specific to individual bacterial species, but universally contain extracellular DNA (eDNA) derived from the bacteria residing within the biofilm. In fact, bacteria of various genera are often part of a shared community architecture of a multispecies biofilm, which requires that the EPS be structurally conducive to all constituent species, but also contain EPS components derived or usable for all resident bacteria. In this regard, the EPS of single and multispecies biofilms contain eDNA scaffolding that appears to be the common structure of the underlying universal EPS. As described herein, Applicants discovered that this eDNA-dependent structure is stabilized by the ubiquitous DNABII family of bacterial DNA-binding proteins. While applicants have shown that exogenous DNA and DNABII proteins can drive free-living (planktonic) bacteria into the community architecture of a biofilm, these two components are insufficient to recapitulate the characteristic eDNA scaffold. Applicants describe herein that polyamines are the third crucial component of the eDNA-DNABIL-dependent universal EPS. Polyamines are short, positively charged organic molecules, ubiquitous both intracellularly and extracellularly that, when bound to DNA, neutralize the polyanionic charge of nucleotide phosphates and allow DNA molecules to condense / aggregate. Importantly, Applicants describe herein that polyamines can drive the more common right-handed B-form DNA into left-handed Z-form DNA, which is nuclease resistant. In fact, although nucleases can prevent the formation of bacterial biofilms, they cannot alter mature biofilms. As biofilms age, the acquisition of nuclease resistance is concomitant with both (1) an increase in polyamines and (2) the appearance of Z-shaped DNA. Described herein are methods for inhibiting the stability of a biofilm, comprising, or alternatively consisting essentially of, or further consisting of contacting the biofilm with an effective amount of an agent that interferes with the binding of a polyamine to DNA. in the biofilm, where the agent is not an HMGB1 protein, a fragment or an equivalent of each. In one aspect, methods of inhibiting the stability of a biofilm comprise, or alternatively consist essentially of, or further consist of contacting the biofilm with an effective amount of one or more agents that interfere with the binding of a polyamine to DNA. in the biofilm. This disclosure also relates to methods of inhibiting the stability of a biofilm, which comprise, or alternatively consist essentially of, or further consist of contacting the biofilm in vitro with an agent that interferes with the binding of a polyamine to DNA in biofilm, wherein the contact comprises, or alternatively consists essentially of, or furthermore consists of coating a surface with an effective amount of cation-depleting agent, wherein the agent is not an HMGB1 protein, fragment or equivalent of each one of them. In one aspect, methods for inhibiting the stability of a biofilm may comprise, or alternatively consist essentially of, or further consist of contacting the biofilm in vitro with an effective amount of an agent that interferes with polyamine DNA binding. in biofilm, wherein the contacting comprises, or alternatively consists essentially of, or further consists of coating a surface with an effective amount of one or more cation-depleting agents. The contact can be in vitro or in vivo. In one embodiment, the agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment. In a second embodiment, the agent comprises, or alternatively consists essentially of, or even further consists of an anti-DNA antibody or fragment or derivative thereof. In a third embodiment, the agent comprises, or alternatively consists essentially of, or further consists of riboflavin, ethidium bromide, bis(methidium)spermine, daunorubicin, TMPyP4, a quaternary benzo[c]phenanthridine alkaloid, quinacrine, 9-amino acridine, or a derivative thereof. In a further embodiment, the agent comprises, or alternatively consists essentially of, or even further consists of chloroquine or a derivative thereof. Further described herein are methods for inhibiting the stability of a biofilm, which comprise, or alternatively consist essentially of, or further consist of contacting the biofilm in vitro with an effective amount of protein Rcncrn / Lznza / YiAi Rcncrn / Lznza / YiAi HMGB1 or biologically active fragment thereof and anti-DNA-B antibody or fragment or derivative thereof, wherein the contacting comprises, or alternatively consists essentially of, or even further consists of coating a surface with an effective amount of HMGB1 protein or biologically active fragment thereof and anti-DNA-B antibody or fragment or derivative thereof. This disclosure also relates to methods of inhibiting the stability of a biofilm, which comprise, or alternatively consist essentially of, or further consist of contacting the biofilm in vitro with an effective amount of chloroquine and anti-DNA-B antibody or fragment or derivative thereof, wherein the contact comprises, or alternatively consists essentially of, or further consists of coating a surface with an effective amount of chloroquine and anti-DNA-B antibody or fragment or derivative thereof. The contact can be in vitro or in vivo. Also provided herein are methods of treating a biofilm in a subject, comprising, or alternatively consisting essentially of, or further consisting of administering to the biofilm-infected subject an effective amount of an agent that interferes with polyamine binding. DNA in the biofilm, where the agent is not an HMGB1 protein, a fragment or an equivalent of each. In one aspect, methods of treating a biofilm in a subject comprise, or alternatively consist essentially of, or further consist of administering to the biofilm-infected subject an effective amount of one or more agents that interfere with the binding of a polyamine to the biofilm. DNA in the biofilm. This disclosure also relates to methods of preventing the formation of a biofilm in a subject susceptible to developing a biofilm, comprising, or alternatively consisting essentially of, or further consisting of administering to the subject an effective amount of an agent that interferes with the binding, of a polyamine to DNA in the biofilm, wherein the agent is not an HMGB1 protein, a fragment or an equivalent thereof. In one aspect, methods of preventing the formation of a biofilm in a subject susceptible to developing a biofilm, comprising, or alternatively consisting essentially of, or even further consisting of administering to the subject an effective amount of one or more agents that interfere with binding of a polyamine to DNA in the biofilm. This disclosure further relates to methods of treating an infection caused by a biofilm-producing bacterium in a subject in need thereof, the method comprising, or alternatively consisting essentially of, or further consisting of administering to the subject an effective amount of an agent , which interferes with the binding of a polyamine to DNA in the biofilm and an agent that inhibits the replication of the organism, wherein the agent is not an HMGB1 protein, a fragment or an equivalent of each. In one aspect, Rcncrn / Lznza / YiAi the methods of treating an infection caused by a bacterium that produces a biofilm in a subject in need thereof, the method comprises, or alternatively consists essentially of, or further consists of administering to the subject an effective amount of one or more plus agents that interfere with the binding of a polyamine to DNA in the biofilm. For any of the methods described above, the polyamine can be selected from the group of: putrescine, spermine, cadaverine, 1,3-diaminopropane or spermidine. In one embodiment, for the methods described above, the agent that interferes with the binding of a polyamine to DNA in the biofilm is a tRNA. In another embodiment, the agent is a polyamine synthesis inhibitor or an agent that inhibits polyamine binding to DNA. In a second embodiment, the agent comprises, or alternatively consists essentially of, or even consists of a polyamine analogue difluoromethylornithine, trans-4-methylcyclohexylamine, sardomozide, methylglyoxal-bis[guanylhydrazone] (MGBG), 1-aminooxy-3-aminopropane, oxaliplatin , cisplatin, dicyclohexylamine, a derivative of any of them, or a salt thereof. In a third embodiment, the agent comprises, or alternatively consists essentially of, or further consists of, a biofilm cation-depleting agent, optionally a cation exchange resin, an aminopolycarboxylic acid, a crown ether, an aza crown, or a cryptand. In a fourth embodiment, the biofilm cation-depleting agent is selected from the group of: sulfonate, sulfopropyl, phosphocellulose, P11 phosphocellulose, heparin sulfate, or a derivative or analogue thereof. In a fifth embodiment, the agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment. In a sixth embodiment, the agent comprises, or alternatively consists essentially of, or even further consists of an anti-DNA-B antibody or fragment or derivative thereof. In an eighth embodiment, the agent comprises, or alternatively consists essentially of, or further consists of riboflavin, ethidium bromide, bis(methidio)spermine, daunorubicin, TMPyP4, a quaternary benzo[c]phenanthridine alkaloid, quinacrine, 9-amino acridine, or a derivative thereof. In a ninth embodiment, the agent comprises, or alternatively consists essentially of, or even further consists of chloroquine or a derivative thereof. In one aspect, the biofilm cation-depleting agent has a net negative charge. In another aspect, the biofilm cation-depleting agent has a net neutral charge. Also provided herein are methods for treating a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF), comprising, or alternatively consisting essentially of, or further consisting of administering an effective amount of an agent that interferes with the conversion of B-DNA to ZDNA in the biofilm or its local environment, wherein the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. The methods for the treatment of Rcncrn / Lznza / YiAi a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF) and / or TB, comprising, or alternatively consisting essentially of, or additionally consisting of administering an effective amount of one One or more agents that interfere with the conversion of B-DNA to Z-DNA in the biofilm or its local environment are described herein, wherein the agent is not an HMGB1 protein, a fragment, or an equivalent of each. In one aspect, the agents are administered in the absence of a DNase. In one embodiment, the agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment. In a second embodiment, the agent comprises, or alternatively consists essentially of, or even further consists of an anti-DNA-B antibody or fragment or derivative thereof. In a third embodiment, the agent comprises, or alternatively consists essentially of, or further consists of riboflavin, ethidium bromide, bis(methidium)spermine, daunorubicin, TMPyP4, a quaternary benzo[c]phenanthridine alkaloid, quinacrine, 9-amino acridine, or a derivative thereof. In a further embodiment, the agent comprises, or alternatively consists essentially of, or even further consists of chloroquine or a derivative thereof. In one aspect, the chloroquine derivative retains the ability to intercalate between DNA bases. Methods for treating a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF), comprising, or alternatively consisting essentially of, or further consisting of administering an effective amount of HMGB1 protein or a biologically active fragment thereof and anti-DNA-B antibody or fragment or derivative thereof are also provided herein. In one aspect, the method of treating a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF) and / or tuberculosis (TB), the method comprising, or alternatively consisting essentially of, or still it also consists of administering an effective amount of chloroquine and anti-DNA-B antibody or fragment or derivative thereof. This disclosure also relates to methods of treating an infection-producing biofilm related to the administration of a platinum-based chemotherapy in a patient receiving or has received the chemotherapy comprising, or alternatively essentially consisting of, or further consisting of administering an effective amount of an agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment, wherein the agent is not an HMGB1 protein, fragment, or equivalent thereof. In one aspect, the method comprises, or alternatively consists essentially of, or even further consists of administering an effective amount of one or more agents that interfere with the conversion of B-DNA to Z-DNA in the biofilm or its local environment. In one aspect, the agents are administered in the absence of a DNase. In a further aspect, the agent comprises, or alternatively consists essentially of, or even further consists of chloroquine or a Rcncrn / Lznza / YiAi derived from it. In a particular aspect, the chloroquine derivative retains the ability to intercalate between DNA bases. In yet a further embodiment, the agent comprises, or alternatively consists essentially of, or even further consists of an anti-DNA antibody or fragment or derivative thereof. In one embodiment, the agent comprises, or alternatively consists essentially of, or further consists of riboflavin, ethidium bromide, bis(methidio)spermine, daunorubicin, TMPyP4, a quaternary benzo[c]phenanthridine alkaloid , quinacrine, 9-amino acridine, or a derivative thereof. This disclosure further relates to methods of treating an infection-producing biofilm related to the administration of a platinum-based chemotherapy in a patient receiving or has received the chemotherapy comprising, or alternatively essentially consisting of, or further consisting of administering an effective amount of HMGB1 protein or biologically active fragment thereof and anti-DNA-B antibody or fragment or derivative thereof. Also provided herein are methods of treating an infection-producing biofilm related to the administration of a platinum-based chemotherapy in a patient receiving or having received chemotherapy comprising, or alternatively consisting essentially of, or further consisting of administering an effective amount of chloroquine and anti-DNA-B antibody or fragment or derivative thereof. The methods described above may further comprise, or alternatively consist essentially of, or further consist of contacting the biofilm, or alternatively administering to the subject, an effective amount of an agent that interferes with the binding of the eDNA to an eDNA-binding protein. DNA and / or an antibacterial agent, wherein the agent is not a HMGB1 protein, a fragment or an equivalent of each. In one aspect, the agent that interferes with the binding of eDNA to the DNA-binding protein comprises, or alternatively consists essentially of, or further consists of one or more of an anti-DNABII antibody, an anti-IHF antibody, and / or an anti-HU antibody, or fragments of each. In one embodiment, the agent that interferes with eDNA binding to a DNA binding protein has a net negative charge. In a second embodiment, the agent that interferes with eDNA binding to a DNA binding protein has a neutral negative charge. In a third embodiment, the agent that interferes with eDNA binding to a DNA binding protein has a net positive charge. In one aspect, the agents are administered in the absence of a DNase. The methods described above can be carried out in the absence of administration of a DNase enzyme. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A, 1B, 1C: Polyamines modulate DNA structure. (Figure 1A) EPS immunofluorescence microscopy image of mucosal biofilm found in the middle ear of chinchilla with acute OM due to NTHI (adapted from Goodman et al. (2011)) ACNCPO I 707 3 / ΥΙΛΙ Mucosal Immunol. 4(6):625-37). Probed for DNABII proteins (gray balls) and eDNA (white regions). DNABII localizes to vertices of eDNA strands in biofilms in vivo. (Figure 1B) Chemical structure of common polyamines (adapted from Di Martino et al. (2013) Int J Med Microbiol. 303(8):484-91). (Figure 1C) Atomic force microscopy image of DNA alone or DNA after incubation with polyamines (adapted from lacomino et al. (2011) Biomacromolecules. 12(4):1178-86). Polyamines induce thick fiber formation and structural complexity in eDNA. Figures 2A, 2B: Polyamines induce the scaffold structure of eDNA. (Figure 2A) EPS immunofluorescence CLSM image of mucosal biofilm found in the middle ear of chinchilla with acute OM due to NTHI. Probed for polyamines (white dots) [putrescine (Put), cadaverine (Cad), spermidine (Spd)] and eDNA (white), counterstained with DAPI (grey regions). Polyamines localize to eDNA strands in biofilms that formed in vivo; spermidine is the most prevalent polyamine in biofilm EPS. (Figure 2B) Transmission electron microscopy images of complexes of DNA (5 pM) and spermidine (700 pM) (top) and DNA (5 pM), spermidine (700 pM) and HU (50 nM) (bottom) (adapted de Sarkar et al (2007) Nucleic Acids Res. 35(3):951-61). Similar structures are formed by DNA-polyamine-IHF complexes. Sarkar et al. (2009) Biochemistry. 48(4):667-75. Polyamines induce DNA condensation and combine with DNABII proteins to form thick fibers. Figures 3A, 3B, 30: Polyamine synthesis inhibitor reduces biofilm formation. (Figure 3A) COMSTAT quantification of LIVE / DEAD®-stained NTHI biofilms grown in the presence of dicyclohexylamine (DCHA, 50 pM), a spermidine synthase (Spd) inhibitor, Spd (1 mM), or both. The bars represent the SEM. Statistical significance compared to control was assessed using t-tests for unpaired data, *P < 0.05. DCHA decreased the average thickness of biofilms, while the simultaneous addition of exogenous Spd restored biofilm formation. (Figure 3B) Immunofluorescence microscopy images of the eDNA scaffold structure in in vitro NTHI biofilms cultured for 3 h in the presence of DCHA (50 pM). Probed for dsDNA (white regions). Production of eDNA scaffold structures is greatly reduced by inhibition of polyamine synthesis. (Figure 3C) Immunofluorescence CLSM images of in vitro NTHI biofilms cultured for 40 h in the presence of DCHA. Probed for Spd (white dots in Figure 3C bottom panel) and stained with DAPI (grey regions). DCHA inhibits the incorporation of polyamines into the EPS biofilm. Figures 4A, 4B: Anti-DNABII disrupts DNABIIpolyamine (PA) dependent structures. (Figure 4A) DNA structures were formed by incubating spermidine (300 μΜ) and HU (1 μΜ) in a buffer containing genomic DNA (gDNA; 2 pg / ml) for 40 h. Immunofluorescence CLSM images of DNABII polyamine-dependent DNA structures. Probed for DNABII proteins (white; indicated on the right side of the image) and counterstained with DAPI (white; indicated on the left side of the image). DNABII polyamine-dependent DNA structures incorporate DNABII proteins. (Figure 4B) EPS structures were formed as in (Figure 4B for 24 h and treated for an additional 16 h with a 1:50 dilution of DNABII antiserum (indicated below the image). DAPI-stained fluorescence CLSM images (white The polyamine-dependent DNA structures of DNABII require DNABII proteins. Figure 5: Phosphocellulose cation exchanger (P11) disrupts NTHI biofilm formation. NTHI biofilm growth was initiated in the basolateral chamber of a transwell plate system while P11 (1%) was added to the apical chamber. Spermidine (1 mM) and HU (1 μΜ) were added at seeding and maintained for 16 h. Biofilms were visualized by CLSM and analyzed by COMSTAT. Average thickness (not shown) showed identical trends. The bars represent the SEM. Statistical significance compared to control was assessed using t-tests for unpaired data, *P<0.05;** P<0.01. P11 prevents the formation of biofilms. Exogenous spermidine and HU together restore biofilm development, but not alone (not shown), suggesting that P11 antibiofilm activity results from titration of structural components (polyamines and DNABII proteins) of EPS of biofilm. Figure 6: Mature biofilms are resistant to DNase disruption. DNase (Pulmozyme; 5 units) was added at seeding (prevention) or at 24 h (disruption) to the respective in vitro preformed biofilms from NTHI and UPEC. After a total of 40 h, biofilms were stained with LIVE / DEAD®, visualized by CLSM, and analyzed by COMSTAT. The bars represent the SEM. Statistical significance compared to control was assessed using unpaired t-tests, *P<0.05;**P<0.01. DNase can prevent, but not disrupt, existing biofilms. Figures 7A, 7B, 7C and 7D: DNABII proteins and polyamines (PAs) interact synergistically to induce DNase resistance. (Figure 7A) Immunofluorescence CLSM images of in vitro NTHI biofilms cultured for 40 h. Tested for spermidine (dark gray beads), HU (light gray beads) and DAPI counterstained (gray regions). Polyamines and DNABII proteins co-localize in the EPS biofilm in vitro (white balls). (Figure 7B) EPS immunofluorescence CLSM image of mucosal biofilm found in the middle ear of chinchilla with acute OM due to NTHI. Tested for putrescine (white balls) and HU (light gray balls), counterstained with DAPI Rcncrn / Lznza / YiAi Rcncrn / Lznza / YiAi (dark gray regions). Polyamines and DNABII proteins co-localize on eDNA strands in biofilms in vivo (white regions). (Figure 7C) Increasing levels of spermidine (Spd) and HU, separately or together, were incubated with genomic DNA (2 pg / ml) for 1.5 h at 37 °C, followed by treatment with Pulmozyme® for 20 min. DNA degradation was assayed using agarose gel electrophoresis. Spd and HU synergistically protect genomic DNA from DNase digestion. (Figure 7D) Spd (300 pM) and HU (1 pM) were incubated with genomic DNA (2 pg / ml) for 40 h, followed by treatment with Pulmozyme® for 20 min. Structures were stained with LIVE / DEAD® and imaged by CLSM (blank). HU-Spd-dependent DNA structures are resistant to DNase treatment. Figures 8A, 8B: DNABII and polyamines are combined to convert the B-DNA form to Z-DNA. (Figure 8A) DNABII-polyamine-dependent DNA structures were formed by incubating genomic DNA (2 pg / ml) with HU (1 pM) and spermidine (300 pM) for 16 h. Immunofluorescence CLSM images of DNABII polyamine-dependent DNA structures. Tested for Z-DNA (white) and stained with DAPI (dark grey). Polyamines and DNABII proteins synergize to induce the conversion of B-DNA to Z-DNA. (Figure 8B) Top: Circular dichroism spectrum of a B-DNA substrate converting to Z-DNA with increasing Z-DNA catalyst concentrations (adapted from Jang et al. (2015) Sci Rep. 5:9943 ). Note the inversion of the negative peak around 250 nm and the positive peak around 280 nm. Bottom: Poly(dGdC) DNA (20 pg / ml) was incubated with HU (15 pM) for 2 h and CD spectra collected. HU shifts the CD spectrum of poly(dGdC) towards a Z-DNA signature. Figure 9: Z-DNA is present within the EPS of the biofilm of multiple human pathogens. Top: Immunofluorescence CLSM images of 40h biofilms of the indicated bacteria, probed without primary antibody (No 1o) or with Z-DNA antibody (blank). Z-DNA is a component of the EPS of multiple bacterial biofilms at different steady-state levels. Bottom: Immunofluorescence CLSM images of indicated biofilms probed with HU (white) and spermidine (dark grey) antibodies, co-localization is (white). DNABII and polyamine components co-localize in the EPS of multiple bacterial biofilms at steady-state levels that correlate with Z-DNA abundance. Figure 10: Z-DNA and polyamines increase in abundance as UPEC and NTHI biofilms mature. Immunofluorescence CLSM images of in vitro biofilms of UTI89 and NTHI at various stages of formation, probed with anti-Z-DNA (white) or anti-spermidine (dark gray). Mature biofilms incorporate an increasing amount of Z-DNA (white) and spermidine (dark gray) within the biofilm EPS over time. Figure 11: HU is required for conversion of B-DNA to Z-DNA and incorporation of polyamines into biofilm EPS. 40 h CLSM immunofluorescence images of wild-type NTHI and the AHU mutant in vitro biofilms, probed with spermidine (dark gray) or anti-Z-DNA (white). In the absence of HU, polyamines and ZDNA are decreased in abundance within the EPS of the biofilm. Figure 12: Nontypeable Haemophilus influenzae biofilms were grown for 40 h in supplemented BHI medium on 8 chambered cover glass slides at 37°C and 5% CO2. Biofilms were washed, probed with the indicated primary antibodies, a fluorescent secondary antibody (dark gray dots), and stained with DAPI (grey regions). Note: The minimal dark gray staining in the lower left image represents the background. Putrescine, spermidine, and spermine were present throughout the biofilm matrix. Figure 13: Nontypeable Haemophilus influenzae were grown for 16 h in supplemented BHI medium containing additives as indicated above in 96-well plates at 37°C and 5% CO2. Growth was quantified by spectrophotometric absorbance at 490 nm (left) and by enumeration of colony-forming units (right). Spermidine synthase inhibitor did not affect normal growth. Figure 14: Nontypeable Haemophilus influenzae biofilms were grown for 40 h in supplemented BHI medium containing additives as indicated under each bar on 8-chamber coverslip slides at 37°C and 5% CO2. Biofilms were washed, stained with LIVE / DEAD®, fixed, and imaged by CLSM. Biofilm parameters were quantified using COMSTAT software. Dicyclohexylamine inhibited biofilm biogenesis, whereas exogenous spermidine was able to rescue biofilm growth. Figure 15: Biofilms of nontypeable Haemophilus influenzae were grown for 40 h in supplemented BHI medium containing additives as indicated above on 8 chambered coverslip slides at 37°C and 5% CO2. Biofilms were washed, probed with primary antibodies directed toward spermidine, a fluorescent secondary antibody (dark gray dots), and stained with DAPI (grey regions). The spermidine synthase inhibitor reduced the presence of spermidine in the biofilm matrix. Figure 16: Surface-adhered nontypable Haemophilus influenzae were grown for 3 h in supplemented BHI medium containing additives as indicated above on Fluorodish coverslip plates at 37°C and 5% CO2. Biofilms were washed, tested with primary antibodies directed against double-stranded DNA and a Rcncrn / Lznza / YiAi fluorescent secondary antibody (white). The spermidine synthase inhibitor reduced both the presence and the complexity of the extracellular DNA structure within the biofilm matrix. Figures 17A, 17B, 17C and 17D: Spermidine is present within the EPS of the biofilm formed by multiple human pathogens. (Figure 17A). Immunofluorescence CLSM images of indicated biofilms probed with HU (light grey) and spermidine (dark grey) antibodies, co-localization is white. The DNABII and polyamine components co-localize in the EPS of multiple bacterial biofilms at steady-state levels. (Figure 17B) Inhibition of spermidine biosynthesis by dicyclohexylamine (DCHA) reduces spermidine levels in NTHI and UPEC biofilms indicated by a decrease in Fl signal, and results in a significant decrease in average thickness compared to with the sBHI control (Figure 17C). UPEC represented as percentage change average thickness compared to LB control (Figure 17D). Figures 18A, 18B: Phosphocellulose has a dose-dependent negative effect on biofilm formation and stability of preformed NTHI biofilm in vitro. (Figure 18A) Biofilm growth was initiated and then maintained for 24 hours and then treated for 16 hours with 0 (SBHI Control), 0.1%, 1% and 5% (w / v) Phosphocellulose (P11) . (Figure 18B) Biofilm growth was initiated and then maintained for 40 hours in the presence of 0 (sBHI control), 0.1%, 1% and 5% (w / v) of (P11). Biofilms were washed with saline and stained with LIVE / DEAD® stain. The images were analyzed by COMSTAT to calculate the average thickness and biomass. All images were captured with a 63X objective. Figure 19: Heparin Sepharose has a negative effect on NTHI biofilm formation in vitro. Biofilm growth was initiated and then maintained for 40 hours in the presence of 0 (sBHI control) or 5% (w / v) heparin sepharose resin. Biofilms were washed with saline and stained with LIVE / DEAD® stain. The images were analyzed by COMSTAT to calculate the average thickness and biomass. All images were captured with a 63X objective. Figure 20: Exogenous addition of HL) rescues the negative effect of phosphocellulose on NTHI biofilm stability in vitro. Biofilm growth was initiated and maintained for 24 hours, then treated for 16 hours as indicated. Biofilms were washed with saline and stained with LIVE / DEAD® stain. The images were analyzed by COMSTAT to calculate the mean thickness and biomass and compared with the sBHI control. All images were captured with a 63X objective. The bars represent the SEM. Statistical significance compared to control Rcncrn / Lznza / YiAi Rcncrn / Lznza / YiAi was assessed using t-tests for unpaired data, *P<0.05;** P<0.01. Figure 21: Exogenous addition of MgCI2 rescues the negative effect of phosphocellulose on NTHI biofilm stability in vitro. Biofilm growth was initiated and maintained for 24 hours then treated for 16 hours as indicated. Biofilms were washed with saline and stained with LIVE / DEAD® stain. The images were analyzed by COMSTAT to calculate the average thickness and biomass. All images were captured with a 63X objective. Figure 22: Exogenous addition of spermidine rescues the negative effect of phosphocellulose on NTHI biofilm stability in vitro. Biofilm growth was initiated then maintained for 24 hours then treated for 16 hours as indicated. Biofilms were washed with saline and stained with LIVE / DEAD® stain. The images were analyzed by COMSTAT to calculate the average thickness and biomass. All images were captured with a 63X objective. Figure 23: The cation depletion effects of P11 phosphocellulose do not require direct contact with the biofilm. Biofilm growth was initiated in the basolateral chamber of a transwell plate system while 0, 0.5, 1, or 1.5% (w / v) phosphocellulose P11 was added to the apical chamber and maintained for 16 hours. Biofilms were washed with saline and stained with LIVE / DEAD® stain. Images were analyzed by COMSTAT to calculate mean thickness and biomass and compared to the sBHI control. All images were captured with a 63X objective. The bars represent the SEM. Statistical significance compared to control was assessed using t-tests for unpaired data, *P<0.05;** P<0.01. Figure 24: Exogenous addition of spermidine reduces the cation depleting effects of P11 phosphocellulose without requiring direct contact with biofilm. Biofilm growth was initiated in the basal chamber of a transwell plate system while 0 or 1.5% (w / v) phosphocellulose P11 was added to the apical chamber and maintained for 16 hours in the presence of 100, 500, or 1000 uM spermidine Biofilms were washed with saline and stained with LIVE / DEAD® stain. Images were analyzed by COMSTAT to calculate mean thickness and biomass and compared to the sBHI control. All images were captured with a 63X objective. The bars represent the SEM. Statistical significance compared to control was assessed using t-tests for unpaired data, *P<0.05;** P<0.01. Brackets indicate a statistical comparison between conditions. Figure 25: Exogenous addition of spermidine and DNABII reduces the cation depleting effects of P11 phosphocellulose without direct contact with biofilm. Biofilm growth was initiated in the basolateral chamber of a plate system. Rcncrn / Lznza / YiAi transwell while adding 0 or 1.5% (w / v) P11 phosphocellulose to the apical chamber and maintained for 16 hours in the presence of 100 uM spermidine or 500 nM HU or in combination. Biofilms were washed with saline and stained with LIVE / DEAD® stain. Images were analyzed by COMSTAT to calculate mean thickness and biomass and compared to the sBHI control. All images were captured with a 63X objective. The bars represent the SEM. Statistical significance compared to control was assessed using t-tests for unpaired data, *P<0.05;** P<0.01. Brackets indicate a statistical comparison between conditions. Figures 26A, 26B: Coating of abiotic surfaces with cation exchange resin prevents biofilm formation in a dose-dependent manner. Chamber slides were coated with solutions of P11 phosphocellulose (Figure 26A) or heparin sepharose (Figure 26B) as indicated. Biofilm growth was initiated and maintained for 40 hours on coated slides. Biofilms were washed with saline and stained with LIVE / DEAD® stain. The images were analyzed by COMSTAT to calculate the average thickness and biomass. All images were captured with a 63X objective. The bars represent the SEM. Figure 27: Mature biofilms are resistant to DNase disruption. DNase (Pulmozyme; 5 units) was added at seeding (prevention) or at 24 h (disruption) to the respective in vitro preformed NTHI or UPEC biofilms. After a total of 40 h, biofilms were stained with LIVE / DEAD®, visualized by CLSM, and analyzed by COMSTAT. The bars represent the SEM. Similar trends were observed for biomass. Statistical significance compared to control was assessed using t-tests for unpaired data, *P<0.05;**P<0.01. DNase can prevent, but not disrupt, existing biofilms. Figure 28: Z-DNA and polyamines increase in abundance as UPEC and NTHI biofilms mature. Immunofluorescence CLSM images of UPEC and NTHI biofilms formed in vitro at various stages of maturation, tested with anti-Z-DNA (light grey) or anti-spermidine (dark grey). Mature biofilms incorporate an increasing amount of Z-DNA (light gray) and spermidine (dark gray) within the biofilm EPS over time. Figure 29: ^ZDNA is present in biofilms of mature pathogenic fungi. Immunofluorescence CLSM images of biofilms formed by Candida albicans in vitro, counterstained with DAPI and probed with anti-B-DNA, anti-Z-DNA or non-primary (light grey). Biofilms from mature fungi incorporate Z-DNA (light grey) within the EPS of the biofilm. Figure 30: Anti-Z-DNA antibodies stimulate biofilm biogenesis. Anti-Z-DNA antibodies (1 mg) were added to NTHI in vitro biofilms during seeding. After 16 h, biofilms were stained with LIVE / DEAD®, visualized by CLSM, and analyzed by COMSTAT. The bars represent the SEM. Similar trends were observed for biomass. Statistical significance compared to control was assessed using paired t-tests. Anti-ZDNA antibodies stabilize the biofilm extracellular matrix, stimulating biofilm biogenesis, whereas anti-B-DNA (eg, anti-dsDNA) antibodies do not stimulate biofilm biogenesis. Figure 31: DNase degrades B-DNA, but not Z-DNA, within the biofilm extracellular matrix. DNase (Pulmozyme; 5 units) was added 24 h after biofilm seeding to preformed NTHI biofilms in vitro. After a total of 40 h, biofilms were probed with anti-Z-DNA, anti-B-DNA, or no primary antibodies, which were revealed using the corresponding secondary fluorescent antibodies and visualized by CLSM. DNase treatment degrades the eDNA structures of the B-DNA form, but reveals an extensive Z-DNA form of eDNA within the extracellular matrix of the biofilm. Figure 32: Z-DNA formation protects DNA from nuclease degradation. A poly(dG-dC) substrate was incubated with salt activated nuclease (SAN) or DNase I in increasing concentrations of NaCI, spermine or spermidine as indicated above. Degradation products were visualized by gel electrophoresis. The high salt content and polyamines protect the DNA from degradation by conversion to the Z-DNA form. Figure 33: DNABII proteins and polyamines are co-localized within the extracellular matrix of the biofilm. Nontypable Haemophilus influenzae biofilms were grown in supplemented BHI medium on 8-well chamber glass slides at 37°C and 5% CO2. Biofilms were washed, probed with primary antibodies against DNABII proteins (light grey) or polyamines (dark grey), a fluorescent secondary antibody, stained with DAPI (grey regions) and visualized by fluorescence microscopy. Polyamines co-localized with HU but not with IHF in the biofilm matrix. An NTHI strain unable to produce HU reduced the accumulation of polyamines in the biofilm matrix. DNABII proteins and polyamines interact to stabilize the extracellular matrix of the biofilm. Figures 34A, 34B: DNABII proteins protect DNA by changing to the ZDNA form. (Figure 34A) A poly(dG-dC) substrate was incubated with DNase I in increasing concentrations of NTHi HU as indicated above. the products of Rcncrn / Lznza / YiAi Rcncrn / Lznza / YiAi degradation were visualized by gel electrophoresis. HU protected the DNA from degradation. (Figure 34B) Top: Circular dichroism spectrum of a B-DNA substrate that converts to Z-DNA with increasing Z-DNA catalyst concentrations (adapted from JRahmouni (1992) Mol Microbiol. 6(5):569 -72.). Note the inversion of the negative peak around 250 nm and the positive peak around 280 nm. Bottom: Poly(dGdC) DNA (5 pg) was incubated with HU (15 μΜ) for 2 h and CD spectra collected. HU shifts the CD spectrum of poly(dGdC) towards a Z-DNA signature. Figures 35A, 35B, 35D: DNABII proteins and polyamines (PAs) interact synergistically to induce DNase resistance. (Figure 35A) Increasing levels of spermidine (Spd) and HU, separately or together, were incubated with genomic DNA (gDNA; 2 pg / ml) for 1.5 at 37 °C, followed by treatment with Pulmozyme® for 20 min. DNA degradation was assayed using agarose gel electrophoresis. Spd and HU synergistically protect genomic DNA from DNase digestion. (Figure 35B) Spd (300 μΜ) and HU (1 pM) were incubated with genomic DNA (2 pg / ml) for 40 h, followed by treatment with Pulmozyme® for 20 min. Frameworks were stained with LIVE / DEAD® and imaged by CLSM (blank). (Figure 35C) EPS immunofluorescence CLSM image of mucosal biofilm found in chinchilla middle ear with experimental OM due to NTHI. Probed for putrescine (dark gray) and HU (light gray), counterstained with DAPI (grey). HU-Spd-dependent DNA structures are resistant to DNase treatment. Polyamines and DNABII proteins co-localize on eDNA strands in biofilms in vivo (blank). (Figure 35D): Increasing concentrations of DNase were added for 16 h into seeding (Prevention) or at 24 h (Disruption) to NTHI or UPEC biofilms. Biofilms were stained, fixed, visualized by CLSM, and analyzed by COMSTAT. The bars represent the SEM. Statistical significance compared to control (no DNase) was assessed by unpaired t-tests, **P<0.01. DNase can prevent the formation of existing biofilms, but not break them. Figure 36: ^ZDNA is present within the EPS biofilm of multiple human pathogens. Top: Immunofluorescence CLSM images of 40-h biofilms formed by the indicated bacteria, probed without primary antibody (no. 1o) or with Z-DNA-specific antibody (light grey). Z-DNA is a component of the EPS of multiple bacterial biofilms at different steady-state levels. Bottom: Immunofluorescence CLSM images of indicated biofilms probed with HU (light grey) and spermidine (dark grey) antibodies, co-localization is (white). DNABII and polyamine components co-localize in the EPS of multiple bacterial biofilms at steady-state levels that correlate with Z-DNA abundance. Figure 37: HMGB1 disrupts Z-DNA structures in the biofilm extracellular matrix. Biofilms of nontypable Haemophilus influenzae were grown in supplemented BHI medium on 8 chambered coverslip slides at 37°C and 5% CO2. After 24 h, the biofilms were treated as above. After 40 h, biofilms were washed, probed with primary antibodies directed against Z-DNA (light gray dots), a fluorescent secondary antibody, stained with DAPI (grey regions), and visualized by fluorescence microscopy. HMGB1 treatment reduced Z-DNA structures in the biofilm matrix. Figures 38A, 38B, 38C: HMGB1 displaces DNABII proteins thus disrupting NTHI biofilms. Biofilms of nontypable Haemophilus influenzae were grown in supplemented BHI medium on 8 chambered coverslip slides at 37°C and 5% CO2. After 24 h, the biofilms were treated as indicated. (Figure 38A) After 40 h, biofilms were washed, probed with primary antibodies directed against DNABII proteins (light gray dots), a fluorescent secondary antibody, stained with DAPI (grey regions), and visualized by fluorescence microscopy. (Figure 38B) Biofilm culture media was collected and analyzed by Western blotting with a primary antibody that recognizes DNABII proteins. HMGB1 treatment displaced DNABII proteins from the biofilm matrix. (Figure 38C) COMSTAT quantification of NTHI biofilms stained with LIVE / DEAD® and visualized with confocal microscopy after treatment with 5 mg / mL HMGB1. HMGB1 disrupts biofilms by displacing DNABII proteins. Figures 39A, 39B: HMGB1 promotes biofilm resolution in an experimental model (chinchilla host) of OM. Diluent or 5 pg of rHMGBI or mHMGBI were administered directly to the middle ear of chinchillas at 4 and 5 days after NTHI infection. Animals were sacrificed 24 hours later and their mid-ears were imaged (Figure 39A) and blind scored (Figure 39B) based on the criteria described at the bottom of (Figure 39A). The bars represent the SEM. ***p<0.001. Imaging and scoring demonstrate that HMGB1 promoted the removal of pre-existing NTHI biofilms in situ. Figures 40A, 40B, 40C: HMGB1 disrupts Burkholderia cenocepacia biofilms. (Figure 40A) B. cenocepacia biofilms were grown in LB medium on 8 chambered coverslip slides at 37°C and 5% CO2. After 24 h, biofilms were treated with 5 mg / mL of HMGB1. After a total of 40 h, biofilms were stained with LIVE / DEAD®, visualized by CLSM, and analyzed by COMSTAT. The bars represent the SEM. (Figure 40B) C57BL / 6 mice were infected with 107 CFU i.t. and simultaneously received 5 mg of rHMGBI or mHMGBI, a non-inflammatory variant of C45S. B. cenocepacia aggregates were visible by fluorescence microscopy Rcncrn / Lznza / YiAi Rcncpn / Lznza / YiAi in sections probed with an a-B antibody. cenocepacia (gray). After 18 h, (Figure 40C) the CFUs were quantified in BAL. The bars represent the SD. *P<0.05, ***P<0.001. HMGB1 treatment significantly alters B. cenocepacia biofilms in situ. Figure 41: HMGB1 reverts polyamine-induced Z-DNA to a nuclease-responsive B-DNA state. A poly(dG-dC) substrate was incubated with spermidine and HMGB1. Degradation products were visualized by gel electrophoresis. HMGB1 treatment restored nuclease sensitivity to spermidine-induced Z-DNA substrates. Figures 42A, 42B, 42C and 42D: Both DNABII proteins and polyamines are required to rescue cation exchanger (P11) mediated biofilm prevention. (Figure 42A) NTHI biofilm growth was initiated at 37°C, 5% CO2 in the basolateral chamber of a transwell plate system, while P11 resin was added to the apical chamber and incubated for 16 h. (Figure 42B) Biofilms were stained, fixed, visualized by CLSM, and analyzed by COMSTAT. The bars represent the SEM. Statistical significance compared to control (not P11) was assessed by unpaired t-tests,****P<0.0001. (Figure 42C) Spermidine (Spd, 300 μΜ) and HU (500 nM) were added at seeding. Biofilms were quantified as in (Figure 42B). **P<0.01, ***P<0.001, and ****P<0.0001 compared to Control (not P11). (Figure 42D) Representative images of biofilms formed under the conditions quantified in (Figure 42C), mean biomass in upper right. The addition of P11 prevents biofilm formation in a dose-dependent manner. Exogenous spermidine and HU together restore biofilm development, but not by themselves, suggesting that the anti-biofilm activity of P11 is a result of titration of structural components (polyamines, DNABII proteins) away from the EPS of biofilm without direct contact. Figures 43A, 43B: Specificity of DNA-B and DNA-Z antibodies. (FIG. 43A) Brominated genomic DNA (2 pg / ml) and polydGdC were incubated in buffer and the absorbance values ​​at 260 nm and 295 nm were measured and the A260 / 295 ratio was calculated. A ratio > 8.6 indicates B-DNA (dark gray), while a value close to 3.2 indicates Z-DNA (white). (FIG. 43B) An ELISA plate was coated with 1 pg of poly dGdC (DNA-B) or brominated poly dGdC (DNA-Z Hindler et al. (2013) J Clin Microbiol. 51(6):1678-84.) , followed by blocking with 0.5% BSA. Wells were then probed with mouse IgG1 (ms) (neg. control), mouse anti-B-DNA or mouse anti-Z-DNA and detected with a secondary goat anti-mouse IgGHRP. TMB (3,3', 5,5'-tetramethylbenzidine) was the colorimetric substrate used for HRP detection (dark gray wells). Anti-B and antiRcncrn / Lznza / YiAi antibodies Z were specific for their respective DNA forms. Figure 44: DNABII proteins, polyamines, and eDNA (B- and Z-DNA) consistently accumulate within the EPS of NTHI biofilms over time. Immunofluorescence CLSM images of NTHI biofilms at various stages of formation, tested with anti-DNA-B (light gray; first from left), anti-spermidine (light gray; second from left), anti-DNABII (light gray; ; third from left), or anti-Z-DNA (white; fourth from left). Mature biofilms incorporate an increasing amount of each TEDS component into the EPS over time. Figure 45: Polyamines and DNABII proteins stimulate Z-DNA, which is resistant to DNase. Immunofluorescence images of the EPS scaffold mimetic formed de novo by addition of DNABII protein (HUNTHI, 500 nM) and spermidine (300 μΜ) to purified genomic DNA (2 μg / ml) and incubation at 37°C for 16 h. Biofilm scaffold mimetics were incubated with Pulmozyme® (DNAse, 5 U / ml) for 1 hour and then probed for B-DNA (dark gray) and Z-DNA (white). Scale bar 10 μΜ. B-DNA and Z-DNA were observed within the mimetic structures, and the addition of DNase selectively removed the B-DNA while the Z-DNA remained intact. Thus, polyamines and DNABII proteins can induce the DNase resistance state by converting eDNA from B-DNA to Z-DNA. Figure 46: TEDS and Z-DNA are present within the EPS of the biofilm formed by multiple human pathogens. (A) Top: Immunofluorescence CLSM images of the indicated biofilms probed with naive or anti-HU (grey) and anti-spermidine (Spd, light gray) antibodies, co-localization is white. Bottom: Immunofluorescence CLSM images of biofilms formed over 40 h of the indicated bacteria, probed with naive or anti-B-DNA (dark gray) and anti-Z-DNA (white) antibodies. A well characterized Z-DNA specific monoclonal antibody (clone Z22 Heydorn et al. (2002) COMSTAT. Microbiology; 146; Yang et al. (2017) Paediatr Respir Rev. 21:65-7; Xu et al. (2016) Molecules;21(8).) was used to detect Z-DNA. DNABII, polyamines, Z-DNA and B-DNA components are present in the EPS of multiple bacterial biofilms. Z-DNA is an integral part of the EPS of multiple bacterial biofilms at different steady-state levels. Figures 47A, 47B: Z-DNA is present in samples in vivo and ex vivo. Left: Z-DNA (white) and B-DNA (dark grey) within (Figure 47A) NTHI biofilm during NTHI-induced experimental OM and (Figure 47B) sputum from a patient with cystic fibrosis. Inset, negative control. Scale bar 10 pm. Right: DNABII protein (grey) and spermidine (Spd, light grey) within (Figure 47A) NTHI biofilm during NTHI-induced experimental OM and (Figure 47B) sputum from a patient with cystic fibrosis. Inset, negative control. Scale bar 10 pm. The components DNABII, polyamines, Z-DNA, and B-DNA are present in chinchilla middle ear sections infected with NTHI biofilms. Z-DNA is an integral part of the EPS of multiple bacterial biofilms at different steady-state levels. Figures 48A, 48B: Z-DNA in biofilms forms a nuclease resistant scaffold. (Figure 48A) Biofilms formed over 24 h by the indicated bacteria (Kp = K. pneumoniae) were incubated with DNase (Pulmozyme®; 40 U / ml) for a further 16 h. Biofilms were then probed with anti-B-DNA (dark gray) and anti-Z-DNA (white) antibodies and counterstained with FM4-64™ bacterial cell membrane stain (not shown). (Figure 48B) Changes in the abundance of DNA-B or DNA-Z were quantified using ImageJ by calculating the ratio of fluorescence intensity of DNA-B or DNA-Z after DNase addition divided by the intensity of fluorescence in the absence of DNase (Control). Fluorescence intensity was normalized to the fluorescence signal from cells stained with FM4-64™. Bars represent SEM. Statistical significance compared to control (no DNase, dotted line) was assessed by paired t-tests, *P<0.05; ****P<0.0001. While B-DNA is degraded by DNase, Z-DNA is resistant and serves to maintain the structural integrity of the biofilm EPS. Figure 49: Z-DNA stabilization stimulates biofilm formation. Biofilm growth of NTHI and UPEC was initiated in the presence of naïve or anti-Z-DNA antibodies (5 mg / ml) for 16 h. Biofilms were stained, fixed, visualized by CLSM, and analyzed by COMSTAT. The bars represent the SEM. Statistical significance compared to control was assessed using t-tests for unpaired data, *P<0.05,**P<0.01. Anti-Z-DNA antibodies stimulate biofilm formation in a dose-dependent manner, whereas naïve antibodies do not. Figures 50A, 50B: The equilibrium shift of B-DNA to Z-DNA conversion alters biofilm formation. NTHI biofilms formed over 24 h were incubated with cerium chloride (CeCI3) or chloroquine for an additional 16 h and probed with neat DNA or anti-Z-DNA (blank) by immunofluorescence CLSM. (Figure 50A) The representative image of the NTHI biofilm indicated an increase in the abundance of Z-DNA upon the addition of 1 mM CeCh. (Figure 50B) The representative image of the NTHI biofilm indicated a decrease in Z-DNA abundance upon the addition of μΜ chloroquine 1. Figures 51A, 51B: The equilibrium shift of B-DNA to Z-DNA conversion alters biofilm formation. NTHI biofilms formed over 24 h were Rcncrn / Lznza / YiAi Rcncrn / Lznza / YiAi incubated with cerium chloride (CeCh) (Figure 51A) or chloroquine (Figure 51B) for an additional 16 hours. Z-DNA was measured by IF and CLSM using anti-Z-DNA and cells were stained with FM4-64 membrane stain. The bars represent the SEM. Statistical significance compared to control was assessed by paired t-tests, *P<0.05,**P<0.01. CeCh increased Z-DNA and biofilm formation, while chloroquine reduced Z-DNA and biofilm development. Figures 52A, 52B: RNA homeostasis modulates development of bacterial biofilms. (Figure 52A) NTHI biofilm growth was initiated in the presence of RNase A for 16 h. Biofilms were stained, fixed, visualized by CLSM, and analyzed by COMSTAT. The addition of RNase A stimulated biofilm formation in a dose-dependent manner, probably through the release of polyamines, a critical catalyst for the extracellular conversion of B-DNA to Z-DNA. (Figure 52B) NTHI biofilms formed for 16 h were incubated with tRNA and analyzed as in (Figure 52A). Guanosine monophosphate (GMP) served as a negative control. The bars represent the SEM. Statistical significance compared to control (no RNase A or tRNA / GMP) was assessed by paired t-tests, *P<0.05, **P<0.01. Addition of tRNA (but not GMP) disrupted early NTHI biofilms in a dose-dependent manner, probably by sequestering polyamines from the EPS biofilm. Figure 53: DNABII and polyamines synergize to convert B-DNA to Z-DNA. In one aspect, the agents are administered in the absence of a DNase. Left: Genomic DNA (2pg / mL) was incubated with spermidine (spd:300pg / mL), HU (500 nM), a combination of spd and HU for 2 h at 37°C. Incubation of gDNA with 3.6 M NaCI was used as a Z-DNA positive control. Medium: gDNA (2 pg / ml) was incubated with increased concentrations of cerium chloride (CeCI3) which is known to induce Z-DNA. Right: poly(dGdC) (1 pg) was incubated with NaCI (3.6 M), chloroquine (100 μΜ), or a combination of NaCI and chloroquine. Chloroquine prevents the transition from B-DNA to Z-DNA. The absorbance values ​​at 260 nm and 295 nm were measured and the A260 / 295 ratio was calculated. A ratio > 8.6 indicates B-DNA, while a value close to 3.2 indicates Z-DNA. DNABII and polyamines, as well as CeCh, synergized to induce Z-DNA, while chloroquine prevented Z-DNA conversion according to a well-established and verified spectroscopic absorbance ratio assay. DETAILED DESCRIPTION OF THE INVENTION Unless otherwise defined, all scientific and technical terms used in this document have the same meanings as are commonly understood by one skilled in the art to which this disclosure pertains. All nucleotide sequences provided herein are presented in the 5' to 3' direction. Although any methods and materials similar or equivalent to those described in this document may be used in practices or Rcncrn / Lznza / YiAi In evidence of the present disclosure, particular non-limiting exemplary methods, devices and materials are now described. All patent and technical publications cited herein are incorporated herein by reference in their entirety. Nothing herein should be construed as an admission that disclosure is not entitled to predate such disclosure by virtue of prior invention. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of tissue culture, immunology, molecular biology, microbiology, cell biology, and recombinant DNA, which are within the skill of the art. See, for example, Sambrook and Russell eds, (2001) Molecular Cloning: A Laboratory Manual, 3rd Edition; the Ausubel et al. eds. (2007) Current Protocols in Molecular Biology; the series Methods in Enzymology (Academic Press, Inc., N.Y.); MacPherson et al. (1991) PCR 1: A Practical Approach (IRL Press at Oxford University Press); MacPherson et al. (1995) PCR 2: A Practical Approach; Harlow and Lane eds. (1999) Antibodies, A Laboratory Manual; Freshney (2005) Culture of Animal Cells: A Manual of Basic Technique, 5th Edition; Gait ed. (1984) Oligonucleotide Synthesis; US Patent No. 4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds, (1987) Gene Transfer Vectors for Mammalian Cells (Coid Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); and Herzenberg et al. eds (1996) Weir's Handbook of Experimental Immunology. All numerical designations, for example, pH, temperature, time, concentration, and molecular weight, including ranges, are approximations that are varied (+) or (-) in increments of 1.0 or 0.1, as appropriate or alternatively by a variation of + / - 15%, or alternatively 10% or alternatively 5% or alternatively 2%. It should be understood, though not always explicitly stated, that all numerical designations are preceded by the term approximately. It should also be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents thereof are known in the art. As used in the specification and claims, the singular forms one, one, and he / she include plural references unless the context clearly indicates otherwise. For example, the term a polypeptide includes a plurality of polypeptides, including mixtures thereof. As used herein, the term "comprising" is intended to mean that "cncpni znzq / YiAi compositions and methods include the listed items, but do not exclude others." When used to define compositions and methods, "consisting essentially of" shall mean to exclude other elements of any meaning essential to the combination for the intended use. Therefore, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the method of isolation and purification and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. "Consisting of" shall mean excluding more than trace elements from other ingredients and substantial steps in the method of administering the compositions described herein. The modalities defined by each of these transition terms are within the scope of this description. A "biofilm" is understood to mean an organized community of microorganisms that sometimes adhere to the surface of a structure, which can be organic or inorganic, together with the polymers such as DNA that they secrete and / or release. Biofilms are highly resistant to microbiotic and antimicrobial agents. They live in gingival tissues, teeth, and restorations, causing caries and periodontal disease, also known as periodontal plaque disease. They also cause chronic middle ear infections. Biofilms can also form on the surface of dental implants, stents, catheter lines, and contact lenses. They grow on pacemakers, heart valve replacements, artificial joints, and other surgical implants. The Centers for Disease Control) estimate that more than 65% of nosocomial (hospital-acquired) infections are caused by biofilms. They cause chronic vaginal infections and lead to life-threatening systemic infections in people with weakened immune systems. Biofilms are also involved in numerous diseases. For example, cystic fibrosis patients have Pseudomonas infections that often result in antibiotic-resistant biofilms. The term inhibit, compete or titrate is intended to reduce the formation of the DNA / protein matrix which is a component of a microbial biofilm. A DNABII polypeptide or protein refers to a DNA-binding protein or polypeptide that is composed of DNA-binding domains and thus has a specific or general affinity for microbial DNA. In one aspect, they bind to DNA in the minor groove. Non-limiting examples of DNABII proteins are an integrating host factor (IHF) protein and a histone-like protein from E. coli strain U93 (HU). Other DNA-binding proteins that may be associated with biofilm include DPS (Genbank Accession No.: CAA49169), H-NS (Genbank Accession No.: CAA47740), Hfq (Genbank Accession No.: ACE63256 ), CbpA (Genbank Accession No.: BAA03950) and CbpB (Genbank Accession No.: NP-418813). Rcncrn / Lznza / YiAi An IHF protein host integrating factor is a bacterial protein used by bacteriophages to incorporate their DNA into host bacteria. They also bind extracellular microbial DNA. The genes encoding the IHF protein subunits in E. coli are himA (Genbank Accession No.: POA6X7.1) and himD (POA6Y1.1) genes. Homologs of these genes are found in other organisms, and peptides corresponding to these genes from other organisms are described in the art, for example, in Table 10 of US Patent No. 8,999,291. HMGB1 is a high mobility cluster box (HMGB1 protein that is reported to bind to and distort the minor groove of DNA and is an example of an agent. Recombinant or isolated protein and polypeptide are commercially available from Atgenglobal, ProSpecBio, Proteinl and Abnova HMGB1 is a small protein of 215 amino acids (approximately 30 Kda) composed of 3 domains: two positively charged domains, box A and B, each comprising 80 amino acids and a negatively charged carbocyl terminus, the tail. Acidic C consisting of approximately 30 consecutive aspartate and glutamate residues A non-limiting example of a wild-type HMGB1 polypeptide sequence is given below: MGKGDPKKPRRKMSSYAFFVQTCREEHKKKHPDASVNFSEFSKKCSERWKTMSAKEKGK FED MAKAD KARYEREM KTYI_PPKG ETKKKF _KDPNAPKRPPSAFFLFCSE YRPKIKGEHPG LSIGDVAKKLGEMWNNTAADDKQPYEKKAEKLKEKYEKDIAAYRAKGWKAPDAAEKEEKKED DEEEEEEDEEEDEEEDDDDE Amino acids in bold (amino acids 1-70) represent the Box A domain. Amino acids in italics (amino acids 88-164) represent the Box B domain. The underlined amino acids (amino acids 186-215) represent the C tail domain. These are non-limiting examples of fragments, for example, the A box domain, the B box domain, the A and B box domains (box domain AB) the C tail domain and the N domain (amino acids 1-185). In one aspect, the fragment consists essentially of the C-terminal domain or a polypeptide comprising the Box B domain. HU or E. coli strain U93 histone-like protein refers to a class of heterodimeric proteins typically associated with E. coli. HU proteins are known to bind to DNA junctions. Related proteins have been isolated from other microorganisms. The complete amino acid sequence of E. coli HU was reported by Laine et al. (1980) Eur. J. Biochem 103(3)447-481. Antibodies against the HU protein are commercially available from Abeam. The term "surface antigens" or "surface proteins" refers to proteins or peptides on the surface of cells such as bacterial cells. Examples of surface antigens are outer membrane proteins such as OMP P5 (Genbank Accession No.: Rcncrn / Lznza / YiAi ΥΡ-004139079.1), ΟΜΡ Ρ2 (Genbank Accession No.: ZZX87199.1), OMP P26 (Genbank Accession No.: YP—665091.1), rsPilA or recombinant soluble PilA (Genbank Accession No.: EFU96734. 1) and Pilin Type IV (Genbank accession No.: Yp_003864351.1). The term Haemophilus influenzae refers to pathogenic bacteria that can cause many different infections, such as ear infections, eye infections, and sinus infections. Many different strains of Haemophilus influenzae have been isolated and have an IhfA gene or protein. Some non-limiting examples of different Haemophilus influenzae strains include Rd KW20, 86-028NP, R2866, PittGG, PittEE, R2846, and 2019. "Microbial DNA" refers to the single- or double-stranded DNA of a microorganism that produces a biofilm. "Inhibiting, preventing or disrupting" a biofilm is intended for the prophylactic or therapeutic reduction of the structure of a biofilm. A '1 bent polynucleotide' refers to a double-stranded polynucleotide that contains a small loop on one strand that does not pair with the other strand. In some embodiments, the loop is from 1 base to about 20 bases long, or alternatively from about 2 bases to about 15 bases long, or alternatively from about 3 bases to about 12 bases long, or alternatively from about 4 bases to about 10 bases long, or alternatively is approximately 4, 5, 6, 7, 8, 9, or 10 bases. A subject of diagnosis or treatment is a cell or an animal, such as a mammal or a human. Non-human animals subject to diagnosis or treatment and are those subject to infections or animal models, for example, apes, murine, such as, rats, mice, chinchilla, canines, such as dogs, leporidae, such as rabbits, cattle, sporting animals, and pets. The terms subject, host, individual, and patient are used interchangeably herein to refer to animals, typically mammalian animals. Non-limiting examples of mammals include humans, non-human primates (eg, apes, gibbons, chimpanzees, orangutans, monkeys, macaques, and the like), domestic animals (eg, dogs and cats), farm animals (eg, horses , cows, goats, sheep, pigs) and experimental animals (eg mouse, rat, rabbit, guinea pig). In some embodiments, a mammal is a human. A mammal can be any age or at any stage of development (for example, an adult, adolescent, child, infant, or mammal in the womb). A mammal can be male or female. In some embodiments, a subject is a human. The terms protein, peptide, and polypeptide are used interchangeably and in their broadest sense to refer to a compound of two or more amino acid subunits, amino acid analogues, or peptidomimetics. The subunits may be linked by peptide bonds. In another embodiment, the subunit may be linked by other bonds, eg, ester, ether, etc. A protein or peptide must contain at least two amino acids and no limitation is placed on the maximum number of amino acids that can comprise a protein or peptide sequence. As used herein, the term "amino acid" refers to natural and / or unnatural or synthetic amino acids, including glycine and the D and L optical isomers, amino acid analogs, and peptidomimetics. The terms polynucleotide and oligonucleotide are used interchangeably and refer to a polymeric form of nucleotides of any length, deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides can have any three-dimensional structure and can perform any function, known or unknown. The following are non-limiting examples of polynucleotides: a gene or gene fragment (for example, a probe, primer, EST or SAGE tag), exons, introns, messenger RNA (mRNA), blot RNA, ribosomal RNA, RNAi, ribozymes , cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes and primers. A polynucleotide can comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polynucleotide. The nucleotide sequence can be interrupted by non-nucleotide components. A polynucleotide can be further modified after polymerization, such as by conjugation with a tagging component. The term also refers to double-stranded and single-stranded molecules. Unless otherwise specified or required, any embodiment described herein that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to constitute the double-stranded form. A polynucleotide is composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); thymine (T); and uracil (U) for thymine when the polynucleotide is RNA. Therefore, the term polynucleotide sequence is the alphabetical representation of a polynucleotide molecule. This alphabetical representation can be entered into databases on a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology search. The term isolated or recombinant as used herein with respect to nucleic acids, such as DNA or RNA, refers to molecules separated from other DNA or RNA, respectively, that are present in the natural source of the macromolecule and polypeptides. The term isolated or recombinant nucleic acid is intended to include fragments of Rcncrn / Lznza / YiAi nucleic acid that do not occur naturally as fragments and would not occur in the natural state. The term isolated is also used herein to refer to polynucleotides, polypeptides, and proteins that are isolated from other cellular proteins and is intended to encompass both purified and recombinant polypeptides. In other embodiments, the term "isolated" or "recombinant" means separated from constituents, cellular and otherwise, in which the cell, tissue, polynucleotide, peptide, polypeptide, protein, antibody, or fragment(s) thereof, which are normally associated In nature. For example, an isolated cell is a cell separated from tissue or cells of a different phenotype or genotype. An isolated polynucleotide is separated from the 3' and 5' contiguous nucleotides with which it is normally associated in its native or natural environment, eg, on the chromosome. As is apparent to those skilled in the art, a non-naturally occurring polynucleotide, peptide, polypeptide, protein, antibody, or fragment(s) thereof does not require isolation to distinguish it from its naturally occurring counterpart. It is to be inferred without explicit recitation and unless otherwise claimed, that when the present disclosure refers to a polypeptide, protein, polynucleotide, or antibody, an equivalent or a biological equivalent thereof is intended to be within the scope of this disclosure. . As used herein, the term biological equivalent thereof is intended to be synonymous with equivalent thereof when referring to a reference protein, antibody, fragment, polypeptide, or nucleic acid, referring to those having minimal homology while still maintaining the desired structure or functionality. Unless specifically stated herein, it is contemplated that any polynucleotide, polypeptide or protein mentioned herein also includes equivalents thereof. In one aspect, an equivalent polynucleotide is one that hybridizes under stringent conditions to the polynucleotide or complement of the polynucleotide as described herein for use in the described methods. In another aspect, an equivalent antigen-binding antibody or polypeptide refers to one that binds at least 70%, or alternatively at least 75%, or alternatively at least 80%, or alternatively at least 85% , or alternatively at least 90%, or alternatively, at least 95% affinity or greater affinity for a reference antibody or antigen-binding fragment. In another aspect, the equivalent thereof competes for binding of the antibody or antigen-binding fragment to its antigen in a competitive ELISA assay. In another aspect, an equivalent is intended to be at least about 80% homology or identity and, alternatively, at least about 85%, or alternatively at least about 90%, or alternatively at least about 95%, or alternatively 98%. % percent homology or identity and exhibits substantially equivalent biological activity to the reference protein, polypeptide or nucleic acid. Rcncrn / Lznza / YiAi Rcncrn / Lznza / YiAi A polynucleotide or polynucleotide region (or a polypeptide or polypeptide region) that has a certain percentage (for example, 80%, 85%, 90%, or 95%) of sequence identity with another sequence means that, when aligned, that percentage of bases (or amino acids) are the same when comparing the two sequences. Alignment and percent sequence homology or identity can be determined using software programs known in the art, for example, those described in Current Protocols in Molecular Biology (Ausubel et al., eds. 1987) Supplement 30, section 7.7. 18, Table 7.7.1. In certain embodiments, default parameters are used for alignment. An exemplary non-limiting alignment program is BLAST, which uses predetermined parameters. In particular, exemplary programs include BLASTN and BLASTP, using the following default parameters: genetic code=standard; filter = none; strand = both; cut= 60; expectation= 10; Matrix= BLOSUM62; Descriptions= 50 sequences; order by = HIGH SCORE; Databases= non-redundant, GenBank+EMBL+DDBJ+PDB+GenBank CDS translations+SwissProtein+SPupdate+PIR. Details of these programs can be found at the following Internet address: ncbi.nlm.nih.gov / cgi-bin / BLAST. Sequence identity and percent identity were determined by incorporating them into clustalW (available from web address: align.genome.jp, last accessed March 7, 2011. Homology or identity or similarity refers to the sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing a position in each sequence that can be aligned for comparison purposes. When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position. A degree of homology between sequences is a function of the number of coincident or homologous positions shared by the sequences. An unrelated or non-homologous sequence shares less than 40% identity, or alternatively, less than 25% identity, with one of the sequences of the present disclosure. Homology or identity or similarity can also refer to two nucleic acid molecules that hybridize under stringent conditions. Hybridization refers to a reaction in which one or more polynucleotides react to form a complex that is stabilized by hydrogen bonding between the bases of nucleotide residues. Hydrogen bonding can occur by Watson-Crick base pairing, Hoogstein junction, or in any other sequence-specific manner. The complex can comprise two strands that form a duplex structure, three or more strands that form a multi-stranded complex, a self-hybridizing single-stranded strand, or any combination of these. A hybridization reaction can be one step in a larger process, such as the initiation of a PCR reaction or the enzymatic cleavage of a polynucleotide by a ribozyme. Examples of stringent hybridization conditions include: incubation temperatures from about 25°C to about 37°C; Hybridization buffer concentrations from about 6xSSC to about 10xSSC; formamide concentrations from about 0% to about 25%; and wash solutions from about 4xSSC to about 8xSSC. Examples of moderate hybridization conditions include: incubation temperatures from about 40°C to about 50°C; buffer concentrations from about 9xSSC to about 2xSSC; formamide concentrations from about 30% to about 50%; and wash solutions from about 5xSSC to about 2xSSC. Examples of high stringency conditions include: incubation temperatures from about 55°C to about 68°C; buffer concentrations from about 1xSSC to about 0.1xSSC; formamide concentrations from about 55% to about 75%; and wash solutions of approximately 1xSSC, O.lxSSC or deionized water. In general, hybridization incubation times are from 5 minutes to 24 hours, with 1.2 or more wash steps, and wash incubation times are about 1, 2, or 15 minutes. SSC is 0.15 M NaCI and 15 mM citrate buffer. It is understood that SSC equivalents can be employed using other damping systems. As used herein, expression refers to the process by which polynucleotides are transcribed into mRNA and / or the process by which transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins. If the polynucleotide is derived from genomic DNA, expression may include mRNA splicing in a eukaryotic cell. The term "encode" as applied to polynucleotides refers to a polynucleotide that is said to encode a polypeptide if, in its native state or when manipulated by methods well known to those skilled in the art, it can be transcribed and / or translated for producing the mRNA of the polypeptide and / or a fragment thereof. The antisense strand is the complement of said nucleic acid, and the coding sequence can be deduced from it. As used herein, the terms treat, treatment and the like are used herein to mean obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic in terms of partial or complete cure of a disorder and / or adverse effect attributable to the disorder. As used herein, treating or treating a disease in a subject may also refer to (1) preventing symptoms or disease from occurring in a subject who is predisposed to or not yet exhibiting symptoms of the disease; (2) inhibit the disease or stop its development; or (3) enhance or cause the Rcncrn / Lznza / YiAi regression of disease or disease symptoms. As understood in the art, treatment is an approach to obtain beneficial or desired results, including clinical results. For the purposes of the present technology, beneficial or desired results may include one or more, but are not limited to, alleviation or amelioration of one or more symptoms, lessening the extent of a condition (including disease), stabilizing (i.e. , not worsening) state of a condition (including disease), retardation or slowing of the condition (including disease), progression, improvement or palliation of the condition (including disease), states and remission (whether partial or complete) , either detectable or undetectable. In one aspect, treatment precludes prophylaxis. When the disease is SLE (systemic lupus erythematosus) and / or cystic fibrosis (CF), evidence for treatment included less evidence of inflammation and / or the level of autoimmune activity or symptoms. Prevention is intended to prevent a disorder or effect in vitro or in vivo in a system or subject that is predisposed to the disorder or effect. An example of this is preventing the formation of a biofilm in a system that is infected with a microorganism known to produce it. A composition means a combination of active agent and another compound or composition, inert (for example, a detectable agent or label) or active, such as an adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservatives, adjuvants, or the like and include pharmaceutically acceptable carriers. Carriers also include protein, peptide, amino acid, lipid, and carbohydrate pharmaceutical excipients and additives (for example, sugars, including monosaccharides, di-, tri-, tetra-oligosaccharides, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars, and the like). and polysaccharides or sugar polymers), which may be present alone or in combination, comprising alone or in combination 199.99% by weight or volume. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid / antibody components, which may also function in a buffering capacity, include alanine, arginine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame. , and the like. Carbohydrate excipients are also intended within the scope of this technology, examples of which include, but are not limited to, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), and myoinositolL «cnccni znzq / YiAi Rcncrn / Lznza / YiAi A pharmaceutical composition is intended to include the combination of an active agent with a carrier, inert or active, making the composition suitable for in vitro, in vivo or ex vivo diagnostic or therapeutic use. "Pharmaceutically acceptable carriers" refers to any diluent, excipient, or carrier that can be used in the compositions described herein. Pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffering substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates , waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool grease. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in the field. They may be selected with respect to the intended form of administration, ie, oral tablets, capsules, elixirs, syrups, and the like, and in accordance with standard pharmaceutical practices. The compositions used in accordance with the disclosure may be packaged in unit dosage form for ease of administration and uniformity of dosage. The term "unit dose" or "dosage" refers to physically discrete units suitable for use in a subject, each unit containing a predetermined amount of the composition calculated to produce the desired responses in association with its administration, ie, the appropriate route and regimen. The amount to be administered, both according to the number of treatments and the unit dose, depends on the desired result and / or protection. The precise amounts of the composition are also at the discretion of the physician and are unique to the individual. Factors affecting the dose include the physical and clinical condition of the subject, the route of administration, the intended goal of treatment (relief of symptoms vs. cure), and the potency, stability, and toxicity of the particular composition. After formulation, the solutions are administered in a manner compatible with the dosage formulation and in an amount such that it is therapeutically or prophylactically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described herein. The term contact means direct or indirect union or interaction between two or more. A particular example of direct interaction is union. A particular example of an indirect interaction is when one entity acts on an intermediate molecule, which in turn acts on the second referenced entity. Contact, as used in this document, includes in Rcncrn / Lznza / YiAi solution, solid phase, in vitro, ex vivo, in a cell and in vivo. Contacting in vivo can be referred to as managing or managing. A biologically active agent or active agent described herein means one or more of an isolated or recombinant polypeptide, an isolated or recombinant polynucleotide, a vector, an isolated host cell, or an antibody, as well as compositions comprising one or more of the same. Administration can be effected in one dose, continuously or intermittently during the course of treatment. Methods for determining the most effective means and dose of administration are known to those skilled in the art and will vary with the composition used for the therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations may be performed with the dose level and pattern selected by the attending physician. Suitable dosage formulations and methods of administration of the agents are known in the art. The route of administration can also be determined and the method of determining the most effective route of administration is known to those skilled in the art and will vary with the composition used for the treatment, the purpose of the treatment, the state of health or the stage of the disease of the disease, subject being treated, and target cell or tissue. Non-limiting examples of the route of administration include oral administration, nasal administration, injection, and topical application. An agent of the present disclosure can be administered for therapy by any suitable route of administration. It will also be appreciated that the optimal route will vary with the condition and age of the recipient and the disease being treated. The term "effective amount" refers to an amount sufficient to achieve the desired effect. In the context of therapeutic or prophylactic applications, the effective amount will depend on the type and severity of the condition in question and the characteristics of the individual subject, such as general health, age, sex, body weight, and tolerance to the pharmaceutical compositions. In the context of an immunogenic composition, in some embodiments, the effective amount is the amount sufficient to result in a protective response against a pathogen. In other embodiments, the effective amount of an immunogenic composition is the amount sufficient to result in the generation of antibodies against the antigen. In some embodiments, the effective amount is the amount necessary to confer passive immunity to a subject in need thereof. With respect to immunogenic compositions, in some embodiments the effective amount will depend on the intended use, the degree of immunogenicity of a particular antigenic compound, and the health / responsiveness of the subject's immune system, in addition to the factors described above. One of skill in the art will be able to determine the appropriate amounts depending on these and other factors. In the case of an in vitro application, in some embodiments the effective amount will depend on the size and nature of the application in question. It will also depend on the nature and sensitivity of the in vitro target and the methods in use. One of skill in the art will be able to determine the effective amount based on these and other considerations. The effective amount may comprise one or more administrations of a composition depending on the modality. A conjugated peptide refers to the association by covalent or non-covalent linkage of one or more polypeptides and another chemical or biological compound. In one non-limiting example, conjugation of a polypeptide to a chemical compound results in improved stability or efficacy of the polypeptide for its intended purpose. In one embodiment, a peptide is conjugated to a carrier, wherein the carrier is a liposome, micelle, or pharmaceutically acceptable polymer. Liposomes are microscopic vesicles consisting of concentric lipid bilayers. Structurally, liposomes vary in size and shape, from long tubes to spheres, with dimensions from a few hundred Angstroms to fractions of a millimeter. Vesicle-forming lipids are selected to achieve a specific degree of fluidity or rigidity of the final complex that provides the lipid composition of the outer layer. These are neutral (cholesterol) or bipolar and include phospholipids such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (Pl), and sphingomyelin (SM) and other types of bipolar lipids including, but not limited to, dioleoylphosphatidylethanolamine (Dioleoylphosphatidylethanolamine), with a hydrocarbon chain length in the range of 14-22, and saturated or with one or more C=C double bonds. Examples of lipids capable of producing a stable liposome, alone or in combination with other lipid components, are phospholipids, such as hydrogenated soy phosphatidylcholine (HSPC), lecithin, phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, cephalin, cardiolipin. , phosphatidic acid, cerebrosides, distearoylphosphatidylethanolamine (DSPE), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), palmitoyltheoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), and dioleoylphosphatidylethanolamine 4-(N-Cycloyl-1-DO-carleimidoxane-thanolamine) ). Additional non-phosphorous containing lipids that can be incorporated into liposomes include stearylamine, dodecylamine, hexadecylamine, isopropyl myristate, triethanolamine lauryl sulfate, alkyl aryl sulfate, acetyl palmitate, glycerol ricinoleate, hexadecyl stearate, amphoteric acrylic polymers, polyethyloxylated fatty acid amides and the aforementioned cationic lipids (DDAB, DODAC, DMRIE, DMTAP, DOGS, DOTAP (DOTMA), DOSPA, DPTAP, DSTAP, DC-Chol). Negatively charged lipids include phosphatidic acid (PA), dipalmitoylphosphatidylglycerol (DPPG), Rcncrn / Lznza / YiAi Rcncrn / Lznza / YiAi dioteoylphosphatidylglycerol and (DOPG), dicetylphosphate that can form vesicles. Typically, liposomes can be divided into three categories based on their overall size and the nature of the lamellar structure. The three classifications, developed by the New York Academy of Sciences Meeting, Liposomes and Their Use in Biology and Medicine, December 1977, are Multilamellar Vesicles (MLV), Small Unilamellar Vesicles (SUVs), and Large Unilamellar Vesicles (LUVs). . Biological active agents may be encapsulated therein for administration in accordance with the methods described herein. A micelle is an aggregate of surfactant molecules dispersed in a liquid colloid. A typical micelle in aqueous solution forms an aggregate with the hydrophilic head regions in contact with the surrounding solvent, sequestering the hydrophobic tail regions in the center of the micelle. This type of micelle is known as a normal phase micelle (oil-in-water micelle). Reverse micelles have head clusters in the center with extended tails (water-in-oil micelles). The micelles can be used to bind a polynucleotide, polypeptide, antibody, or composition described herein to facilitate efficient delivery to the target cell or tissue. The phrase "pharmaceutically acceptable polymer" refers to the group of compounds that can be conjugated to one or more polypeptides described herein. Conjugation of a polymer to the polypeptide is contemplated to be capable of extending the half-life of the polypeptide in vivo and in vitro. Non-limiting examples include polyethylene glycols, polyvinylpyrrolidones, polyvinyl alcohols, cellulose derivatives, polyacrylates, polymethacrylates, sugars, polyols, and mixtures thereof. Biological active agents can be conjugated to a pharmaceutically acceptable polymer for administration according to the methods described herein. A gene delivery vehicle is defined as any molecule that can transport inserted polynucleotides into a host cell. Examples of gene delivery vehicles are liposomes, biocompatible polymers of micelles, including natural polymers and synthetic polymers; lipoproteins; polypeptides; polysaccharides; lipopolysaccharides; artificial viral envelopes; metal particles; and bacteria or viruses, such as baculoviruses, adenoviruses, and retroviruses, bacteriophages, cosmids, plasmids, fungal vectors, and other recombination vehicles typically used in the art that have been described for expression in a variety of eukaryotic and prokaryotic hosts, and that can be used for gene therapy as well as for expression of single proteins. A polynucleotide described herein can be delivered to a cell or tissue using a gene delivery vehicle. Gene delivery, gene transfer, transduction, and the like, as used herein, are terms that refer to the introduction of an exogenous polynucleotide (sometimes referred to as a transgene) into a host "cncpni znzq / YiAi" cell, regardless of method. used for introduction. Such methods include a variety of well-known techniques, such as vector-mediated gene transfer (for example, via viral infection / transfection, or various other protein- or lipid-based gene delivery complexes), as well as techniques that facilitate delivery. of naked polynucleotides (such as electroporation, gene gun delivery, and various other techniques used for introduction of polynucleotides). The introduced polynucleotide may be stable or transiently maintained in the host cell. Stable maintenance typically requires that the introduced polynucleotide contain an origin of replication compatible with the host cell or be integrated into a host cell replicon such as an extrachromosomal replicon (eg, a plasmid) or a nuclear or mitochondrial chromosome. A number of vectors are known to be capable of mediating gene transfer into mammalian cells, as is known in the art and described herein. As used herein, the term eDNA refers to extracellular DNA found as a component of pathogenic biofilms. A plasmid is an extrachromosomal DNA molecule separate from chromosomal DNA that is capable of replicating independently of chromosomal DNA. In many cases, it is circular and double-stranded. Plasmids provide a mechanism for horizontal gene transfer within a population of microbes, and typically provide a selective advantage in a given environmental state. Plasmids may carry genes that provide resistance to natural antibiotics in a competitive environmental niche, or alternatively, the proteins produced may act as toxins in similar circumstances. Plasmids used in genetic engineering are called vector plasmids. Many plasmids are commercially available for such uses. The gene to be replicated inserts copies of a plasmid containing genes that make cells resistant to particular antibiotics and a multiple cloning site (MCS or polylinker), which is a short region containing several restriction sites of common use that allow easy insertion of DNA fragments at this location. Another important use of plasmids is to produce large amounts of protein. In this case, the researchers grow bacteria that contain a plasmid that harbors the gene of interest. Just as the bacterium produces proteins to confer antibiotic resistance, it can also be induced to produce large amounts of protein from the inserted gene. This is an easy and cheap way to mass-produce a gene or the protein it then codes for. A yeast artificial chromosome or YAC refers to a vector used to clone large fragments of DNA (greater than 100 kb and up to 3000 kb). It is an artificially constructed chromosome and contains the telomeric, centromeric, and origin of replication sequences necessary for replication and preservation in yeast cells. Constructed using an initial circular plasmid, they are linearized using restriction enzymes, and then DNA ligase can add a sequence or gene of interest within the linear molecule through the use of sticky ends. Yeast expression vectors, such as YACs, Ylps (yeast integrative plasmid) and YEps (yeast episomal plasmid), are extremely useful as eukaryotic protein products can be obtained with post-translational modifications, since yeast itself is eukaryotic cells; however, YACs have been found to be more unstable than BACs, producing chimeric effects. A viral vector is defined as a recombinantly produced virus or viral particle comprising a polynucleotide for delivery to a host cell, either in vivo, ex vivo, or in vitro. Examples of viral vectors include retroviral vectors, adenovirus vectors, adeno-associated virus vectors, alphavirus vectors, and the like. Vectors based on infectious tobacco mosaic virus (TMV) can be used to make proteins and have been reported to express Griffithsin in tobacco leaves (O'Keefe et al. (2009) Proc. Nat. Acad. Sci. USA 106(15):6099-6104). Alphavirus vectors, such as Semliki Forest virus-based vectors and Sindbis virus-based vectors, have also been developed for use in gene therapy and immunotherapy. See, Schlesinger & Dubensky (1999) Curr. Opinion. Biotechnol. 5:434-439 and Ying et al. (1999) Nat. Med. 5(7):823827. In aspects where gene transfer is mediated by a retroviral vector, a vector construct refers to the polynucleotide comprising the retroviral genome or part thereof, and a therapeutic gene. As used herein, retroviral-mediated gene transfer or retroviral transduction has the same meaning and refers to the process by which a gene or nucleic acid sequences are stably transferred to the host cell by virtue of the virus it enters the cell and integrates its genome into the genome of the host cell. The virus can enter the host cell through its normal infection mechanism or be modified so that it binds to a different host cell surface receptor or ligand to enter the cell. As used herein, "retroviral vector" refers to a viral particle capable of introducing foreign nucleic acid into a cell through a viral or virus-like entry mechanism. Retroviruses carry their genetic information in the form of RNA; however, once the virus infects a cell, the RNA is reverse transcribed into the form of DNA that integrates into the infected cell's genomic DNA. The integrated DNA form is called a provirus. In aspects where gene transfer is mediated by a viral DNA vector, such as an adenovirus (Ad) or adeno-associated virus (AAV), a vector construct refers to the polynucleotide comprising the viral genome or part thereof, and a transgene. adenoviruses Rcncrn / Lznza / YiAi Rcncrn / Lznza / YiAi (Ads) are a relatively well-characterized and homogeneous group of viruses, including more than 50 serotypes. See, for example, PCT International Application Publication No. WO 95 / 27071. Ads do not require integration into the host cell genome. Vectors derived from recombinant Ad have also been constructed, particularly those that reduce the potential for recombination and generation of wild type virus. See, PCT International Application Publication Nos. WO 95 / 00655 and WO 95 / 11984, wild-type AAV has high infectivity and specificity in integrating into the host cell genome. See, Hermonat & Muzyczka (1984) Proc. nati. Acad. Sci. USA 81:6466-6470 and Lebkowski et al. (1988) Mol. Cell. BioL 8:3988-3996. Vectors containing both a promoter and a cloning site into which a polynucleotide can be operatively ligated are well known in the art. Such vectors are capable of transcribing RNA in vitro or in vivo, and are commercially available from sources such as Stratagene (La Jolla, CA) and Promega Biotech (Madison, Wis.). In order to optimize expression and / or transcription in vitro, it may be necessary to delete, add, or alter the 5' and / or 3' untranslated portions of clones to eliminate additional, potentially inappropriate, or alternative translation start codons. other sequences that may interfere with or reduce expression, either at the transcription or translation level. Alternatively, consensus ribosome binding sites can be inserted immediately 5' of the start codon to enhance expression. Gene delivery vehicles also include DNA / liposome complexes, micelles, and targeted viral protein-DNA complexes. Liposomes that also comprise a targeting antibody or a fragment thereof can be used in the methods described herein. In addition to delivery of polynucleotides to a cell or cell population, direct introduction of the proteins described herein into the cell or cell population can be accomplished by the non-limiting technique of protein transfection, alternatively by culturing conditions that can enhance expression and / or or promoting the activity of the proteins described herein are other non-limiting techniques. As used herein, the terms antibody, antibodies, and immunoglobulin include whole antibodies and any antigen-binding fragment or single chain thereof. Thus, the term "antibody" includes any protein or peptide-containing molecule that comprises at least a portion of an immunoglobulin molecule. The terms antibody, antibodies, and immunoglobulin also include immunoglobulins of any isotype, antibody fragments that retain specific binding to antigen, including but not limited to Fab, Fab', F(ab)2, Fv, scFv, dsFv, Fd fragments , dAb, VH, VL, VhH and V-NAR domains; minibodies, diabodies, tribodies, tetrabodies and kappa bodies; multispecific antibody fragments formed from fragments of Rcncrn / Lznza / YiAi antibodies and one or more isolates. Examples of such include, but are not limited to, a heavy or light chain complementarity determining region (CDR) or ligand-binding portion thereof, a heavy or light chain variable region, a constant region of heavy chain or light chain, a framework (FR), or any part thereof, at least a part of a binding protein, chimeric antibodies, humanized antibodies, single chain antibodies, and fusion proteins comprising an antigen-binding part of an antibody and a non-antibody protein. The variable regions of the heavy and light chains of the immunoglobulin molecule contain a binding domain that interacts with an antigen. Antibody constant regions (Abs) can mediate the binding of immunoglobulin to host tissues. The term anti- when used before a protein name, anti-DNABII, anti-IHF, anti-HU, anti-OMP P5, for example, refers to a monoclonal or polyclonal antibody that binds and / or has affinity for a particular protein. For example, anti-IHF refers to an antibody that binds to the IHF protein. The specific antibody may have affinity for or bind to proteins other than the protein against which it was raised. For example, anti-IHF, although it is generated specifically against the IHF protein, can also bind to other proteins that are related by sequence homology or by structural homology. Antibodies can be polyclonal, monoclonal, multispecific (eg, bispecific antibodies), and antibody fragments, as long as they exhibit the desired biological activity. Antibodies can be isolated from any suitable biological source, eg, murine, rat, sheep, and canine. As used herein, "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies. Monoclonal antibodies are highly specific, as each monoclonal antibody is directed against a single antigen determinant. Antibodies can be detectably labeled, for example, with a radioisotope, an enzyme that generates a detectable product, a fluorescent protein, and the like. Antibodies can be further conjugated to other moieties, such as members of specific binding pairs, eg, biotin (biotin-avidin specific binding pair member) and the like. The antibodies may also be attached to a solid support, including, but not limited to, polystyrene bead plates or beds, and the like. Monoclonal antibodies can be generated using hybridoma techniques or recombinant DNA methods known in the art. A hybridoma is a cell that is produced in the laboratory from the fusion of an antibody-producing lymphocyte and a non-antibody-producing cancer cell, usually a myeloma or lymphoma. A hybridoma proliferates and produces a continuous sample of a specific monoclonal antibody. Rcncrn / Lznza / YiAi Alternative techniques for generating or selecting antibodies include in vitro exposure of lymphocytes to antigens of interest and screening of antibody display libraries in cells, phage or similar systems. The term "human antibody," as used herein, is intended to include antibodies that have variable and constant regions derived from human germ-line immunoglobulin sequences. The human antibodies described herein may include amino acid residues not encoded by human germline immunoglobulin sequences (eg, mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody" as used herein is not intended to include antibodies in which germline-derived CDR sequences of another mammalian species, such as a mouse, have been grafted onto human framework sequences. Therefore, as used herein, the term "human antibody" refers to an antibody in which substantially every part of the protein (eg, CDR, framework, CL, Ch domains (eg, Chi, Ch2 , Chs), hinge, (VL, VH)) is substantially non-immunogenic in humans, with only minor sequence changes or variations. Similarly, designated primate (monkey, baboon, chimpanzee, etc.), rodent (mouse, rat, rabbit, guinea pig, hamster, and the like) and other mammalian antibodies designate such species, subgenus, genus, subfamily, antibodies family specific. Additionally, chimeric antibodies include any combination of the above. Such changes or variations optionally retain or reduce immunogenicity in humans or other species relative to unmodified antibodies. Therefore, a human antibody is different from a chimeric or humanized antibody. It is noted that a human antibody can be produced by a non-human animal or a prokaryotic or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin genes (eg, heavy chain and / or light chain). Furthermore, when a human antibody is a single chain antibody, it may comprise a linker peptide not found in native human antibodies. For example, an Fv may comprise a linker peptide, such as two to about eight glycine residues or other amino acids, that connects the heavy chain variable region and the light chain variable region. Such linker peptides are considered to be of human origin. As used herein, a human antibody is derived from a particular germline sequence if the antibody is derived from a system that uses human immunoglobulin sequences, for example, by immunizing a transgenic mouse carrying human immunoglobulin genes or by screening a human immunoglobulin gene. human immunoglobulin gene library. A human antibody that is derived from a germline immunoglobulin sequence Human Rcncrn / Lznza / YiAi can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequence of human germ-line immunoglobulins. A selected human antibody is typically at least 90% identical in amino acid sequence to an amino acid sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as human by comparison to the amino acid sequences of germline immunoglobulin from other species (eg, murine germline sequences). In certain instances, a human antibody may be at least 95%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene. . Normally, a human antibody derived from a particular human germ line sequence will not show more than 10 amino acid differences from the amino acid sequence encoded by the human germ line immunoglobulin gene. In certain instances, the human antibody may show no more than 5, or even no more than 4, 3, 2, or 1 amino acid differences from the amino acid sequence encoded by the germline immunoglobulin gene. A human monoclonal antibody refers to antibodies displaying a single binding specificity that have variable and constant regions derived from human germline immunoglobulin sequences. The term also refers to recombinant human antibodies. Methods for producing these antibodies are described herein. The term recombinant human antibody, as used herein, includes all human antibodies that are prepared, expressed, created, or isolated by recombinant means, such as antibodies isolated from an animal (eg, a mouse) that is transgenic or transchromosomal. for human immunoglobulin, genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the antibody, e.g., from a transfectoma, antibodies isolated from a combinatorial recombinant human antibody library, and antibodies prepared, expressed, created or isolated by any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germ line immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when using a transgenic animal for human Ig sequences, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH regions and VL of the recombinant antibodies are sequences which, while derived from and related to the human germline VH and VL sequences, may not naturally exist within the germline repertoire of human antibodies in vivo. Methods for producing these antibodies are described herein. As used herein, chimeric antibodies are antibodies whose heavy and light chain genes have been constructed, typically by genetic engineering, from antibody constant and variable region genes belonging to different species. As used herein, the term "humanized antibody" or "humanized immunoglobulin" refers to a human / non-human chimeric antibody that contains minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues of a variable region from the recipient are replaced by residues of a variable region from a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primates having the desired specificity, affinity, and ability. Humanized antibodies may comprise residues not found in the recipient antibody or the donor antibody. The humanized antibody may also optionally comprise at least a portion of an immunoglobulin (Fe) constant region, typically that of a human immunoglobulin, a non-human antibody that contains one or more amino acids in a framework region, constant region, or a CDR, which have been substituted by an amino acid from a human antibody at the corresponding position. In general, humanized antibodies are expected to produce a reduced immune response in a human host, compared to a non-humanized version of the same antibody. Humanized antibodies can have conservative amino acid substitutions that have substantially no effect on antigen binding or other antibody functions. Conservative substitution groups include: glycine-alanine, valinaleucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, serine-threonine, and asparagine-glutamine. The terms polyclonal antibody or polyclonal antibody composition as used herein refer to a preparation of antibodies that are derived from different B cell lines. They are a mixture of secreted immunoglobulin molecules against a specific antigen, each of which recognizes a different epitope. As used herein, the term "antibody derivative" encompasses a full-length antibody or a fragment of an antibody, wherein one or more of the amino acids is chemically modified by alkylation, pegylation, acylation, ester formation, or ester formation. amide or the like, for example, to link the antibody to a second molecule. This includes, but is not limited to, pegylated antibodies, cysteine ​​pegylated antibodies, and variants thereof. Rcncrn / Lznza / YiAi Rcncrn / Lznza / YiAi As used herein, the term "tag" means a directly or indirectly detectable compound or composition that is directly or indirectly conjugated to the composition to be detected, for example, N-terminal histidine (N-His) tags, isotopes magnetically active, eg, 115Sn, 117Sn, and 119Sn, a non-radioactive isotope such as 13C and 15N, polynucleotide, or protein such as an antibody to generate a labeled composition. The term also includes sequences conjugated to the polynucleotide that will provide a signal upon expression of the inserted sequences, such as green fluorescent protein (GFP) and the like. The tag can be detectable itself (eg, radioisotope tags or fluorescent tags) or, in the case of an enzymatic tag, can catalyze chemical cleavage of a detectable compound or substrate composition. The tags may be suitable for small-scale detection or more suitable for high-throughput screening. As such, suitable labels include, but are not limited to, magnetically active isotopes, non-radioactive isotopes, radioisotopes, fluorochromes, chemiluminescent compounds, dyes, and proteins, including enzymes. The label can be simply detected or it can be quantified. A response that is simply detected generally comprises a response whose existence is simply confirmed, while a response that is quantized generally comprises a response that has a quantifiable (eg, numerically reportable) value such as intensity, polarization, and / or other property. In luminescence or fluorescence assays, the detectable response can be generated directly using a luminophore or fluorophore associated with an assay component actually involved in binding, or indirectly using a luminophore or fluorophore associated with another component (eg, reporter or reporter). Examples of signal-producing luminescent tags include, but are not limited to, bioluminescence and chemiluminescence. The detectable luminescence response generally comprises a change or appearance of a luminescence signal. Suitable methods and luminophores for luminescently labeling test components are known in the art and are described, for example, in Haugland, Richard P. (1996) Handbook of Fluorescent Probes and Research Chemicals (6taed). Examples of luminescent probes include, but are not limited to, aequorin and luciferases. As used herein, the term "immunoconjugate" encompasses an antibody or antibody derivative associated with or linked to a second agent, such as a cytotoxic agent, a detectable agent, a radioactive agent, a targeting agent, a human antibody, a humanized antibody, a chimeric antibody, a synthetic antibody, a semisynthetic antibody, or a multispecific antibody. Examples of suitable fluorescent labels include, but are not limited to, fluorescein, rhodamine, tetramethylrhodamine, eosin, erythrosine, coumarin, methylcoumarins, Rcncrn / Lznza / YiAi pyrene, malazite green, stilbene, Lucifer Yellow, Cascade Blue™ and Texas Red. Other suitable optical dyes are described in the Haugland, Richard P. (1996) Handbook of Fluorescent Probes and Research Chemicals (6th ed.). In another aspect, the fluorescent tag is functionalized to facilitate covalent attachment to a cellular component present in or on the surface of the cell or tissue, such as a cell surface tag. Suitable functional groups include, but are not limited to, isothiocyanato groups, amino groups, haloacetyl groups, maleimides, succinimidyl esters, and sulfonyl halides, all of which can be used to attach the fluorescent tag to a second molecule. The choice of the functional group of the fluorescent tag will depend on the binding site of a linker, agent, marker or second tag agent. Eukaryotic cells comprise all kingdoms of life except monera. They can be easily distinguished through a membrane-bound nucleus. Animals, plants, fungi, and protists are eukaryotes, or organisms whose cells are organized into complex structures by internal membranes and a cytoskeleton. The most characteristic membrane-bound structure is the nucleus. Unless specifically indicated, the term "host" includes a eukaryotic host, including, for example, yeast cells, higher plants, insects, and mammals. Non-limiting examples of eukaryotic cells or hosts include apes, bovines, porcine, murine, rats, birds, reptiles, and humans. Prokaryotic cells that normally lack a nucleus or any other membrane-bound organelle and are divided into two domains, bacteria and archaea. In addition to chromosomal DNA, these cells can also contain genetic information in a circular loop called an episome. Bacterial cells are very small, about the size of an animal mitochondria (about 1-2 pm in diameter and 10 pm long). Prokaryotic cells have three main shapes: rod-shaped, spherical, and spiral. Instead of going through elaborate replication processes like eukaryotes, bacterial cells divide by binary fission. Examples include but are not limited to Bacillus bacteria, E. coli bacteria, and Salmonella bacteria. A native or natural antigen is an epitope-containing polypeptide, protein or fragment, which has been isolated from a natural biological source, and which can specifically bind to an antigen receptor, in particular a T cell antigen receptor (TCR). ), in a subject. The terms antigen and antigenic refer to molecules with the ability to be recognized by an antibody or otherwise act as a member of an antibody-ligand pair. Specific binding refers to the interaction of an antigen with the variable regions of the immunoglobulin heavy and light chains. Antibody-antigen binding Rcncrn / Lznza / YiAi can occur in vivo or in vitro. One of skill in the art will understand that macromolecules, including proteins, nucleic acids, fatty acids, lipids, lipopolysaccharides, and polysaccharides, have the potential to act as an antigen. One skilled in the art will further understand that nucleic acids encoding a protein with the potential to act as an antibody ligand necessarily encode an antigen. The skilled person will further understand that antigens are not limited to full length molecules, but may also include partial molecules. The term antigenic is an adjectival reference to molecules that have the properties of an antigen. The term encompasses substances that are immunogenic, ie, immunogens, as well as substances that induce immune unresponsiveness, or anergy, ie, anergens. An altered antigen is one that has a primary sequence that is different from that of the corresponding wild-type antigen. Altered antigens can be prepared by synthetic or recombinant methods and include, but are not limited to, antigenic peptides that are differentially modified during or after translation, for example, by phosphorylation, glycosylation, cross-linking, acylation, proteolytic cleavage, binding to a antibody molecule, membrane molecule, or other ligand. (Ferguson et al. (1988) Ann. Rev. Biochem. 57:285-320). A synthetic or altered antigen described herein is intended to bind to the same TCR as the wild-type epitope. Immune response broadly refers to the antigen-specific responses of lymphocytes to foreign substances. The terms immunogen and immunogenic refer to molecules with the ability to elicit an immune response. All immunogens are antigens, however not all antigens are immunogenic. An immune response described herein can be humoral (through antibody activity) or cell-mediated (through T cell activation). The response can occur in vivo or in vitro. One of skill in the art will understand that a variety of macromolecules, including proteins, nucleic acids, fatty acids, lipids, lipopolysaccharides, and polysaccharides, have the potential to be immunogenic. The person skilled in the art will further understand that nucleic acids encoding a molecule capable of eliciting an immune response necessarily encode an immunogen. One of skill will further understand that immunogens are not limited to full length molecules, but may include partial molecules. The term passive immunity refers to the transfer of immunity from one subject to another through the transfer of antibodies. Passive immunity can occur naturally, such as when maternal antibodies are transferred to the fetus. Passive immunity can also occur artificially such as when antibody compositions are administered to non-immune subjects. Antibody donors and recipients can be human or non-human subjects. Antibodies can be polyclonal or monoclonal, can be generated in vitro or in vivo, and can be purified, partially purified, or non-purified depending on the modality. In some embodiments described herein, passive immunity is conferred on a subject in need thereof by administration of antibodies or antigen-binding fragments that specifically recognize or bind a particular antigen. In some embodiments, passive immunity is conferred by administration of an isolated or recombinant polynucleotide encoding an antibody or antigen-binding fragment that specifically recognizes or binds a particular antigen. In the context of this disclosure, a ligand is a polypeptide. In one aspect, the term "ligand" as used herein refers to any molecule that binds to a specific site on another molecule. In other words, the ligand confers the specificity of the protein in a reaction with an immune effector cell or an antibody to a protein or DNA to a protein. In one aspect, it is the ligand site within the protein that combines directly with the complementary binding site on the immune effector cell. As used herein, the term "inducing an immune response in a subject" is a term well understood in the art and is intended to mean an increase of at least about 2-fold, at least about 5-fold, at least about 10-fold, at least approximately 100-fold, at least approximately 500-fold, or at least approximately 1000-fold or more in an immune response to an antigen (or epitope) can be detected or measured, after introducing the antigen (or epitope) into the subject, relative to with the immune response (if any) prior to the introduction of the antigen (or epitope) into the subject. An immune response to an antigen (or epitope) includes, but is not limited to, the production of an antigen-specific (or epitope-specific) antibody and the production of an immune cell that expresses a binding molecule on its surface. specifically to an antigen (or epitope). Methods for determining whether an immune response to a given antigen (or epitope) has been induced are well known in the art. For example, the antigen-specific antibody can be detected using any of a variety of immunoassays known in the art, including, but not limited to, ELISA, where, for example, the binding of an antibody in a sample to an immobilized antigen (or epitope) is detected with a detectably labeled second antibody (eg, enzyme-labeled mouse anti-human Ig antibody). As used herein, "solid phase support" or "solid support", used interchangeably, is not limited to a specific type of support. Rather, a large number of supports are available and known to those skilled in the art. Solid phase supports include silica gels, resins, derivatized plastic films, glass bead beds, cotton, plastic beads, alumina gels. As used in this document, Rcncrn / Lznza / YiAi Rcnccn / Lznza / YiAi solid support also includes matrices, cells and liposomes presenting synthetic antigens. A suitable solid phase support can be selected based on the desired end use and suitability for various protocols. For example, for the synthesis of peptides, the solid phase support can refer to resins such as polystyrene (for example, PAM resin obtained from Bachem Inc., Peninsula Laboratories, etc.), POLYHIPE® resin (obtained from Aminotech, Canada), polyamide resin (obtained from Peninsula Laboratories), polyethylene glycol-grafted polystyrene resin (TentaGel®, Rapp Polymere, Tubingen, Germany), or polydimethylacrylamide resin (obtained from Milligen / Biosearch, Calif.). An example of a solid phase support includes glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite. The nature of the carrier can be soluble to some extent or insoluble. The support material can have virtually any possible structural configuration as long as the coupled molecule is capable of binding to a polynucleotide, polypeptide, or antibody. Thus, the support configuration can be spherical, as in a bead, or cylindrical, as in the inner surface of a test tube, or the outer surface of a rod. Alternatively, the surface may be flat, such as a sheet, test strip, etc. or, alternatively, beds of polystyrene beads. Many other suitable carriers for antibody or antigen binding will be known to those skilled in the art, or will be able to determine the same using routine experimentation. The term modulate an immune response includes inducing (increasing, provoking) an immune response; and reduce (suppress) an immune response. An immunomodulatory method (or protocol) is one that modulates an immune response in a subject. Ways of making the disclosure I. Biofilm structure and disease The reservoir of bacteria that sustain chronic and recurrent bacterial infections resides in a biofilm, a community of bacteria that have become attached to a surface and, when in this state, can resist removal by the host's immune system as well as by the antimicrobials. In fact, bacteria in a biofilm state are typically >1000 times more resistant to antibiotics than the same bacteria in a free-living or planktonic state. Ceri et al. (1999) J Clin Microbiol. 37(6):1771-6. The ability of biofilm bacteria to resist clearance is primarily due to self-made semi-permeable matrix or extracellular polymeric substances (EPS) that act as a physical barrier to environmental hazards, as well as create conditions for altered physiology. it limits metabolism to enhance this resilient state. Although the components of the EPS are specific to each bacterium and include proteins, polysaccharides, lipids and nucleic acids, the nature of the EPS Rcncrn / Lznza / YiAi should be conducive enough for bacterial genera in general to interact productively (eg, as metabolic partners). To this end, several recent discoveries have led to the possibility of an underlying universal EPS structure common to all eubacteria. Whitchurch and colleagues (Whitchurch et al. (2002) Science. 295(5559)) demonstrated that extracellular DNA (eDNA) was a common component of EPS and that DNase treatment of bacteria was sufficient to prevent biofilm formation. While this result was replicated for multiple genera, the use of DNase failed to treat existing biofilms more than one to two days after biofilm seeding despite the fact that eDNA is evident in biofilms throughout their growth cycle. life. Separately, applicants previously identified DNABII proteins, the only nucleoid-associated protein (NAP) family that is common to all eubacteria, as a necessary component of eDNA-dependent EPS. Indeed, antibodies directed against DNABII proteins titrate DNABII proteins from the bulk medium and thus shift the balance of DNABII proteins from the eDNA-bound to the free state, resulting in a catastrophic collapse of all DNABII proteins. bacterial biofilms tested to date, and includes mixed-species biofilms. Goodman et al. (2011) Mucosal Immunol. 4(6):625-37; Novotny et al. (2013) PLoS One. 8(6):e67629; Devaraj et al. (2015) Mol Microbiol. 96(6):1119-35; Rocco et al. (2017) Mol Oral Microbiol. 32(2):118-30; Gustave et al. (2013) J Cyst Fibros. 12(4):384-9; Novotny et al. (2016) EBioMedicine. 10:33 a.m. m.-44. Importantly, unlike DNase, antibody treatment directed against DNABII proteins is effective at all stages of biofilm development, demonstrating that eDNA-dependent EPS is a critical structure regardless of the age of the biofilm. the biofilm. Brockson et al. (2014) Mol Microbiol. 93(6):1246-58. Despite knowing that eDNA and DNABII family members are essential components of the EPS, understanding the full structure of the EPS has proven elusive; DNABII proteins and DNA are insufficient to recapitulate the functional structures of EPS in vitro. Applicants describe herein that for multiple human pathogens that as the biofilm matures, eDNA-dependent EPS is dependent on both DNABII proteins and polyamines, such that eDNA changes from a B-DNA to B-DNA conformation. -Z. This last result is particularly intriguing, as it probably explains the failure of DNase to disrupt mature biofilms; nucleases only cleave the more classical B form of DNA. intracellular bacterial nucleoid The DNA within bacteria is highly structured and facilitates the regulation of all forms of nucleic acid processes including DNA replication, repair, transcription, and recombination. Unlike eukaryotic cells, bacteria ECnCPO I 707 3 / ΥΙΛΙ lack histones. Instead, bacterial DNA is structured in part by a class of proteins called nucleoid-associated proteins (NAPs). NAPs collectively bind to DNA to create functional structures. Dillon et al. (2010) Nat Rev Microbiol. 8(3):185-95. Among the multiple NAP members that exist in all genera, only the DNABII family is ubiquitous among all eubacteria. Dey et al. (2017) Mol Phylogenet Evol. 107:356-66. The DNABII family of proteins function as dimers (homodimers or heterodimers depending on the species) and includes the histone-like proteins HU and IHF. HLJ binds weakly and nonspecifically to and doubles double-stranded DNA (dsDNA), but has a much higher affinity for prefolded or structured dsDNA3. IHF like HU binds and folds DNA with a strong preference for prefolded / structured DNA. Unlike HU, IHF is only expressed by proteobacteria and also has a preference for a specific DNA consensus sequence. Swinger et al. (2004) CurrOpin Struct Biol. 14(1):28-35. Extracellular bacterial nuclei Extracellular DNA (eDNA) has been known to have a biological function since the transforming principle was discovered to be the result of DNA. Avery et al. (1944) J Exp Med. 79(2):137-58. In fact, eDNA is also essential for the extracellular matrix (extracellular polymeric substances, EPS) of bacterial biofilms. Gunn et al. (2016) J Biol Chem. 291(24):12538-46. However, the structure of the biofilm eDNA and the importance of that structure for eDNA function has so far not been investigated. Chronic and recurrent infections are the result of bacterial biofilms. While biofilms are further distinguished from planktonic bacteria by intercellular communication and transport systems, their most distinctive feature is their self-manufactured EPS that protect resident biofilm bacteria by acting as a semi-permeable barrier and creating an environment for altered / slowed metabolism; in fact, biofilm bacteria are 1,000 times more resistant to antibiotics than their planktonic counterparts. Ceri et al. (1999) J Clin Microbiol. 37(6):1771-6. Interestingly, the EPS of each bacterium are distinct and consist of a variety of proteins, lipids, polysaccharides, and nucleic acids. Gunn et al. (2016) J Biol Chem. 291(24):12538-46. However, while biofilms may consist of a single species, commonly in chronic infections, and invariably in the environment, they are composed of multiple genera and as such need to be able to interact productively (eg coaggregation with specific metabolic partners Stacy et al. al (2016) Nat Rev Microbiol 14(2):93-105 Wolcott et al (2013) Clin Microbiol Infect 19(2):107-12). This community concept implies that despite the variable composition of EPS, each EPS must be sufficiently adaptable to allow divergent bacteria to interact within the biofilm, and further suggests that biofilm EPS likely have an underlying structure. universal. eDNA-dependent EPS have the qualities of a universal underlying architecture Multiple groups have examined the eDNA associated with bacterial biofilms from human and ecological genera and observed a scaffold structure (Figure 1A). Jurcisek et al. (2017) Proc Nati Acad Sci USA. 114(32):E6632-E41; Sena-Velez et al. (2016) PLoS One. 11(6) :e0156695; Wang et al. (2015) Environ Microbiol Rep. 7(2):330-40. Whitchurch and colleagues first demonstrated that P. aeruginosa biofilms could be prevented by deoxynuclease I (DNAse) treatment (Whitchurch et al. (2002) Science. 295(5559)), indicating that eDNA is a critical structural component of the EPS. While DNase can inhibit early biofilm formation in many genera (Frederiksen et al. (2006) Acta Paediatr. 95(9):1070-4; Martins et al. (2012) Mycoses. 55(1):805; Hymes et al (2013) J Infected Dis 207(10):1491-7), biofilms become recalcitrant to DNase over time even though eDNA clearly persists as the biofilm matures. Goodman et al. (2011) Mucosal Immunol. 4(6):625-37; Hall-Stoodley et al. (2008) BMC Microbiol. 8:173; Izano et al. (2009) Microb Pathog. 46(4):207-13; Kaplan et al. (2012) J Antibiotic (Tokyo). 65(2):73-7; Novotny et al. (2013) PLoS One. 8(6):e67629; Tetz et al. (2010) DNA Cell Biol. 29(8):399-405. While this result has often been interpreted to mean that eDNA is no longer important for the structural integrity of EPS, applicants have shown that eDNA not only persists, but also becomes the primary underlying structure of EPS. . Goodman et al. (2011) Mucosal Immunol. 4(6):625-37; Novotny et al. (2013) PLoS One. 8(6):e67629; Devaraj et al. (2015) Mol Microbiol. 96(6):1119-35; Rocco et al. (2017) Mol Oral Microbiol. 32(2):118-30; Brockson et al. (2014) Mol Microbiol. 93(6):1246-58. The DNABII family of proteins is the backbone that maintains the structural integrity of biofilm eDNA scaffolded EPS Applicants have previously shown that the ubiquitous DNABII proteins, and probably no other NAPs (Devaraj et al. (2017) Microbiologyopen.), are structural constituents of eDNA and that once removed, the eDNA structure breaks down. Goodman et al. (2011) Mucosal Immunol. 4(6):625-37; Novotny et al. (2013) PLoS One. 8(6):e67629; Devaraj et al. (2015) Mol Microbiol. 96(6):1119-35; Rocco et al. (2017) Mol Oral Microbiol. 32(2):118-30. Indeed, DNABII proteins were found to specifically bind to the vertices (prefolded DNA) of the eDNA scaffold of biofilms formed in vivo, while antibodies directed against DNABII proteins are sufficient to undermine the structure of the scaffolded EPS. of eDNA and as a result causes a catastrophic collapse of biofilms of one or more species for each species applicants have examined (Goodman et al. (2011) Mucosal Immunol. 4(6):625-37; Novotny et al. ( 2013) PLoS One. Rcncrn / Lznza / YiAi Rcncpn / Lznza / YiAi 8(6):e67629; Devaraj et al. (2015) Mol Microbiol. 96(6):1119-35; Rocco et al. (2017) Mol Oral Microbiol. 32(2):118-30), despite the maturity of the biofilm. Brockson et al. (2014) Mol Microbiol. 93(6):1246-58. This rupture releases resident bacteria in a planktonic and therefore antimicrobial and immunologically sensitive state (Goodman et al. (2011) Mucosal Immunol. 4(6):625-37; Novotny et al. (2013) PLoSOne. 8(6 ):e67629; Brockson et al. (2014) Mol Microbiol. 93(6):1246-58), demonstrating the importance and universality of this family of proteins in biofilm structure. Given the known interactions of the DNABII family with DNA, it was unexpected that applicants could not create conditions with only DNABII DNA and proteins that would recapitulate the three-dimensional scaffold-like structures observed in bacterial biofilms. Polyamines are ubiquitous both intracellularly and extracellularly and are required for the eDNA-scaffolded EPS structure of biofilms. Polyamines are typically short organic molecules that contain multiple positively charged (basic) primary amines at neutral pH and are commonly derived from the decarboxylation of amino acids. (Figure 1B). Michael et al. (2016) Biochem J. 473(15):2315-29. Polyamines are ubiquitous in nature, concentrations as high as mM are found both intra and extracellularly (Tabor et al. (1985) Microbiol Rev. 49(1):8199) being spermidine, spermine and putrescine the most abundant. Although polyamines are involved in multiple processes in bacterial physiology, they are perhaps most important for eDNA-scaffolded EPS for 5 reasons. First, they bind to DNA and neutralize the negative charge on the phosphate backbone and, as a result, alter the structure of DNA. Bachrach et al. (2005) Curr Protein Pept Sci. 6(6):559-66; Pasini et al. (2014) Amino Acids. 46(3):595-603. Second, while polyamines tend to promote protein-DNA interactions at low concentrations (mM), they tend to interfere at higher concentrations (mM), an exception being DNABII-DNA interactions that cause DNA to form thick fibers. Sarkar et al. (2009) Biochemistry. 48(4):667-75; Sarkar et al. (2007) Nucleic Acids Res. 35(3):951 61. Third, polyamine synthesis has been found to be induced during biofilm formation and some of these effects occur extracellularly (although only so far examined). date on the bacterial membrane). Wilton et al. (2015) Antimicrob Agents Chemother. 60(1):544-53. Fourth, atomic force microscopy (AFM) experiments to visualize mixtures of polyamines and DNA reveal a structure very similar to biofilm eDNA scaffolds (Figure 1C). Finally, polyamines can induce a conversion of native B-form DNA to Z-form DNA in prone sequences at physiological concentrations (100 μΜ). Thomas et al. (1986) Nucleic Acids Res. 14(16):6721-33; Thomas et al. (1988) J Mol Biol. 201(2):463-7. Conversion of B-DNA to Z-DNA may be a novel means of making resistant Rcncrn / Lznza / YiAi to EPS nuclease with eDNA scaffold and create a stable structural material. AD-B and DNA-Z are distinct conformations of dsDNA that exist in equilibrium, with DNA-B predominating under most physiological conditions. Alternating purines and pyrimidines (particularly dGdC) are more likely to exist as Z-DNA in salt (single molar or divalent cations) or in negative supercoil. Pohl et al. (1983) Cold Spring Harb Symp Quant Biol. 47 Pt 1:113-7; Pohl et al. (1986) Proc Nati Acad Sci USA. 83(14):4983-7. In the latter case, Z-DNA prone regions may briefly juxtapose next to B-DNA during transcription when negative supercoiling is transiently induced. Rahmouni et al. (1992) Mol Microbiol. 6(5):569-72. While B-DNA bases adopt a right-handed helix (10 bp / turn), Z-DNA forms a left-handed helix (12 bp / turn). Jovin et al. (1987) Ann Rev Phys Chem. 38:521-60. B-DNA has two grooves (major and minor), and most interacting proteins recognize / bind to the major groove due to its larger size and discriminating hydrogen bond donors and acceptors for each nucleotide base. In contrast, the main groove is absent in Z-DNA and most of those bonding contacts are found on the convex face. Jovin et al. (1987) Ann Rev Phys Chem. 38:521-60. The Z-DNA has a single groove corresponding to the minor groove of the B-DNA. Interestingly, DNABII proteins are one of the few DNA-binding proteins that bind in the minor groove (Kim et al. (2014) Acta Crystallogr D Biol Crystallogr. 70(Pt 12):3273-89), suggesting that they may bind to Z-DNA. The change of eDNA from B-DNA to Z-DNA is consistent with 4 observations of the EPS with eDNA scaffolding. First, the switch to Z-DNA occurs under the conditions present in the EPS of the biofilm; prone sequences will change to Z-DNA in the presence of physiological concentrations (100 mM) of some polyamines (spermidine and spermine). Second, Z-DNA tends to aggregate and form fibers. Chaires et al. (1988) J Biomol Struct Dyn. 5(6):1187-207. Strong negative charge neutralization (e.g. polyamines) of the phosphate backbone favors Z-DNA since the phosphates in the Z-DNA backbone are closer together than in B-DNA but it is also permissive for DNA aggregation . Third, Z-DNA is stiffer than B-DNA with almost a three-fold increase in persistence length (Thomas et al. (1983) Nucleic Acids Res. 11(6):1919-30) consistent with the straight fibers Applicants observe in the eDNA scaffold (Figures 1A, 1B and 1C, Figures 2A and 2B, Figures 3A, 3B and 3C). And finally, Z-DNA is resistant to nucleases. Unlike the canonical B-DNA binding proteins, there are only a few known proteins that recognize Z-DNA (Athanasiadis et al. (2012) Semin Cell Dev Biol. 23(3):275-80) (however , Z vs B DNA discriminating antibodies are available). Bergen et al. (1987) J Immunol. 139(3):743-8. Interestingly, the Z-DNA binding proteins are homologous, binding ZDNA on B-DNA with 1,000 to 10,000-fold higher affinity. (Herbert et al. (1996) J Biol Rcncrn / Lznza / YiAi Chem. 271(20):11595-8), induce the Z-DNA conformation in prone sequences and, at least in the case of ZBP1, are part of the innate immune system that detects the presence of microbial DNA. Athanasiadis et al. (2012) Semin Cell Dev Biol. 23(3):275-80. Importantly, proteins that use B-DNA as a substrate (for example, nucleases) do not recognize and therefore function on the same DNA sequence in the Z configuration despite Watson base pairing being conserved. Crick. II. A tripartite approach Applicants have previously shown that eDNA-DNABII interactions serve to maintain the structural integrity of biofilm EPS (Goodman et al. (2011) Mucosal Immunol. 4(6):625-37; Novotny et al. (2013) PLoS One. 8(6):e67629; Devaraj et al. (2015) Mol Microbe!. 96(6):1119-35; Rocco et al. (2017) Mol Oral Microbe!. 32(2):118-30 Devaraj et al (2017) Microbiologyopen.; Brockson et al. (2014) Mol Microbiol. 93(6):1246-58), and that disrupting these interactions leads to positive ex vivo results (Gustave et al. (2013) J Cyst Fibras. 12(4):384-9) and in vivo (Goodman et al. (2011) Mucosal Immunol. 4(6):625-37; Novotny et al. (2016) EBioMedicine. 10:33-44 Freire et al (2017) Mol Oral Microbiol 32(1):7488). Although both DNA and DNABII proteins were shown to be necessary, they are not sufficient to recapitulate the architecture of the EPS scaffold. Herein we describe an eDNA-dependent tripartite scaffold (TEDS) of eDNADNABII-dependent EPS that is based on the presence and relative location of (1) eDNA, (2) DNABII proteins, and the recently discovered EPS constituent, (3 ) polyamines. In one aspect, applicants show that in addition to eDNA and DNABII proteins, polyamines are an essential component of the TEDS structure of bacterial biofilms. Second, Applicants show that together, these three components facilitate the formation of a universal EPS that can foster productive interactions between bacterial genera in the protective biofilm state. Third, by using these components, Applicants define and recapitulate this universal structure and provide evidence consistent with observations of thick double-stranded DNA strands, induction of a nuclease-resistant state, and demonstrate whether this state requires Z-DNA as a criterion of resistance. structural valuation. Ultimately, this provides diagnostic and therapeutic interventions that focus on the TEDS structure itself as a target for intervention. A. Polyamines Polyamines work in conjunction with DNABII proteins to direct the assembly of eDNA scaffolds. The chinchilla model of acute otitis media caused by NTHI faithfully recapitulates the course and pathophysiology of the human disease (Bakaletz et al. (2009) Expert RevVaccines. Rcnccn / Lznza / YiAi 8(8):1063-82) and depends on a recalcitrant biofilm in the middle ear. Using this model, Applicants previously demonstrated that DNABII proteins associate with eDNA, which are located at the vertices of eDNA strands (Figure 1A) (Goodman et al. (2011) Mucosal Immunol. 4(6):625- 37) and these eDNA strands appear strikingly similar to polyamines visualized with DNA by AFM (Figure 1C). lacomino et al. (2011) Biomacromolecules. 12(4):1178-86. DNABII proteins bind to DNA in the presence of mM concentrations of spermidine in vitro (Figure 2B), leading to investigation of the possible interaction between DNABII proteins and polyamines to produce a biofilm eDNA scaffold structure. Applicants performed immunofluorescence confocal laser scanning microscopy (CLSM) on sections of fixed and embedded middle ear mucosal biofilms to visualize eDNA-interacting polyamines within the biofilm EPS as Applicants have previously observed for DNABII proteins. Immunofluorescence images show that eDNA and polyamines co-localize along fibers that are present within the mucosal biofilm (Figure 2A) and are visually similar to those observed by Hud and coworkers with DNABII proteins and polyamines in vitro (Sarkar et al. (2009) Biochemistry. 48(4):667-75; Sarkar et al. (2007) Nucleic Acids Res. 35(3):951-61) (Figure 2B). Polyamine biosynthesis is necessary for biofilm structure Applicants investigated whether the broad-acting polyamine biosynthesis inhibitor dicyclohexylamine (DCHA) would alter NTHI biofilm biogenesis in vitro. DCHA inhibits spermidine synthase (Paulin et al. (1986) Antonie Van Leeuwenhoek. 52(6):483-90; Pegg et al. (1983) FEBS Lett. 155(2):192-6), the enzyme that catalyzes conversion of putrescine to spermidine. Although DCHA did not affect NTHI growth (data not shown), DCHA inhibited biofilm biogenesis in vitro, decreasing average thickness and biomass as determined by COMSTAT analysis (Heydorn et al. (2000) Microbiology. 146 ( Pt 10): 2395-407) of CLSM images of NTHI biofilms stained with LIVE / DEAD® (Figure 3A). In addition, applicants found that DCHA inhibited eDNA scaffold production in early biofilm development (Figure 3B), suggesting that polyamine biosynthesis is a necessary step in biofilm formation. In support of these findings, applicants noted that DCHA reduced the incorporation of extracellular polyamines into biofilm EPS by immunofluorescence (Figure 3C), and that defects in biofilm biogenesis could be compensated by the addition of exogenous spermidine (Figure 3C). 3A). Together, these results reveal that the incorporation of polyamines into the EPS is critical for the development and function of the eDNA scaffold to support robust biofilm growth. Anti-DNABII alters the polyamine-dependent DNA structure of DNABII Rcncrn / Lznza / YiAi Immunofluorescence was used to determine if DNABII proteins are incorporated into EPS mimetic structures. Spermidine (300 μΜ) and HU (1 μΜ) were incubated with genomic DNA (2 μg / ml). EPS mimetics were then probed with either naive IgG (control) or anti-DNABII, a fluorescent secondary antibody, stained with DAPI and obtained by CLSM. The DNABII proteins were fully incorporated into the EPS structure (Figure 4A). EPS mimetics were then formed, treated with anti-DNABII antibodies, stained with DAPI, and imaged by CLSM. Sequestration of DNABII proteins with anti-DNABII antibodies to EPS mimetics dramatically reduced the abundance and size of aggregated structures (Figure 4B), which further confirmed DNABII incorporation and its importance for DNA structural stability. Disruption of the NTHI biofilm by the P11 cation exchanger can be prevented by exogenous addition of DNABII (HU) and spermidine Phosphocellulose (P11) is a negatively charged resin that has a high affinity for positively charged molecules such as polyamines and DNABII proteins. To determine the effect of P11 sequestration of these molecules on bacterial biofilm formation, Applicants used a transwell system. NTHI growth was initiated in the basolateral chamber while P11 (1% w / v) was added to the apical chamber at seeding. At 16 h, biofilms were washed and stained with LIVE / DEAD®, imaged using CLSM, and analyzed with COMSTAT. P11 significantly reduced the average thickness and biomass (Figure 5). To determine whether P11 cation depletion included polyamines and / or DNABII proteins, growth of NTHI in the basolateral chamber was initiated with the exogenous addition of 1 mM spermidine and 1 μΜ HU, while P11 was added at 1% w / v to the apical chamber. Both spermidine and HU were necessary structural components of the biofilm matrix and only together prevented biofilm disruption by P11 (Figure 5); individually, HU and spermidine were insufficient (data not shown). DNase cannot disrupt mature pathogenic bacterial biofilms Applicants evaluated the antibiofilm effect of Pulmozyme®, a recombinant human DNase that is used in conjunction with standard therapies for the management of patients with cystic fibrosis (CF) to improve lung function. Yang et al. (2017) Paediatr Respir Rev. 21:65-7. Pulmozyme® was added at seeding (biofilm prevention) or into preformed biofilms (biofilm disruption) (Figure 6). The resulting biofilms were stained with LIVE / DEAD® and evaluated by CLSM and COMSTAT analysis. The addition of DNase at seeding resulted in a significant reduction in the average thickness and biomass of NTHI and UPEC biofilms compared to untreated biofilms (Figure 6). However, DNase was unable to disrupt mature biofilms (Figure 6) suggesting that the Rcncrn / Lznza / YiAi eDNA loses susceptibility to nuclease digestion as biofilms develop. Applicants propose that as biofilms mature, the eDNA is spherically protected from nucleases and / or the eDNA acquires a novel structure that makes it recalcitrant to nuclease digestion. DNABII proteins and polyamines interact synergistically to confer nuclease resistance to DNA. Immunofluorescence of NTHI biofilms tested with anti-DNABII and anti-spermidine antibodies indicated that polyamines co-localize with DNABII proteins in vitro (Figure 7A) and in vivo (Figure 7B). Applicants hypothesized that DNABII and polyamines interact with eDNA synergistically to confer DNase resistance to mature biofilms. To test in vitro synergism, applicants incubated NTHI genomic DNA (gDNA) with spermidine (10, 20, 50, or 100 μΜ) in the presence or absence of HU (50 or 100 nM) and DNase (0.5 units). Degradation was assessed by agarose gel electrophoresis and UV illumination. While spermidine (>100 μΜ) and HU (1 μΜ) individually protected gDNA, lower levels of spermidine (<50 μΜ) and HU (<100 nM) synergistically inhibited gDNA digestion (Figure 7C) suggesting that nuclease resistance is due to the combination of DNABII proteins and polyamines within the biofilm matrix. Next, applicants wanted to test whether the EPS mimetics were resistant to DNase. HU (1 μΜ) and spermidine (300 mM) were incubated with gDNA (2 pg / ml) for 40 h to create an EPS scaffold mimetic, followed by DNase treatment (5 units). As shown by CLSM, these DNABII polyamine-dependent DNA structures were resistant to DNase (Figure 7D), similar to mature biofilms. B. DNABII, polyamines and DNA form Z-DNA in vitro Polyamines cause Z-DNA prone sequences to change the BZ equilibrium to the Z-DNA configuration upon binding (Thomas et al. (1986) Nucleic Acids Res. 14(16):672133; Thomas et al. (1988) J Mol Biol. 201(2):463-7), whereas DNABII proteins fold and condense DNA. Due to the synergism of inhibition by HU and spermidine binding in Applicants' in vitro DNase degradation assays (Figure 7), and the ability of Z-DNA to resist DNase, Applicants hypothesized that mimetic structures of EPS would contain Z-DNA. EPS structures were formed as in Figures 4A and 4B and Figures 7A, 7B, 7C and 7D for 16h with gDNA. Immunofluorescence CLSM was performed with anti-Z-DNA antibody probing, which confirmed the presence of Z-DNA (note white color; Figure 8A). To determine if DNABII proteins influence the B-Z balance, Applicants used circular dichroism (CD). HU DNA and poly(dGdC) substrate mixtures exhibit inversion of the ellipticity peaks of B-DNA alone (250 and Rcncrn / Lznza / YiAi 280 nm) (Jang et al. (2015) Sci Rep. 5:9943), similar to a characteristic Z-DNA spectrum (Figure 8B). EPS in bacterial biofilms contain Z-DNA and polyamines To further characterize the association of Z-DNA and polyamines, applicants performed immunofluorescence on 40-h biofilms. Biofilms of the indicated bacterial pathogens were imaged by CLSM after probing with anti-DNABII and anti-spermidine, or anti-Z-DNA antibodies; while Z-DNA was detected within the biofilm EPS of each of the bacterial pathogens (Figure 9) there was clearly a hierarchy between species (UPEC = Staphylococcus epidermidis < K. pneumoniae < NTHI). In all cases, there was extensive co-localization between DNABII (HU) and spermidine (note the white color), as well as a correspondence with Z-DNA abundance. Applicants further examined biofilms from NTHI and UPEC at various stages of biofilm formation (24, 40, and 90 h) and observed that spermidine and Z-DNA increased concomitantly within the biofilm EPS with age of the biofilm. biofilm (Figure 10). These data suggest that Z-DNA and spermidine are indeed an integral part of the biofilm EPS and likely contribute to its structure and DNase resistance status. HU-deficient NTHI cannot form native biofilms, incorporate polyamines, or induce a B to Z DNA change Since polyamines co-localize with HU within the NTHI biofilm EPS in vitro (Figure 7A and Figure 9) and in vivo (Figure 7B), applicants evaluated the role of HU in incorporating polyamines and Z-DNA within of NTHI Biofilm EPS. HU-deficient NTHI (hupA null; DHU) was compared to WT NTHI biofilms for the presence of polyamines and Z-DNA by immunofluorescence. The lack of HU resulted in a significant reduction of polyamines and Z-DNA within the biofilm EPS compared to WT (Figure 11) suggesting that HU is required for the presence of polyamines and Z-DNA within the EPS. of NTHI biofilm. III. DIAGNOSTIC AND THERAPEUTIC METHODS Provided herein are methods of treating a biofilm in a subject, comprising, or alternatively consisting essentially of, or further consisting of administering to the biofilm-infected subject an effective amount of an agent that interferes with the binding of a polyamine to the biofilm. DNA in the biofilm. In one aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In another aspect, the agent is provided in the absence of a DNase. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In one aspect, methods for treating a biofilm on a subject, comprise, or alternatively consist essentially of, or further consist of Rcncrn / Lznza / YiAi in administering to the subject infected with a biofilm an effective amount of one or more agents that interfere with the binding of a polyamine to DNA in the biofilm. In one aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In another aspect, the agent is provided in the absence of a DNase. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In another aspect, methods of treating a biofilm in a subject comprise, or alternatively consist essentially of, or further consist of administering to the biofilm-infected subject an effective amount of two or more agents that interfere with the binding of a polyamine to the biofilm. DNA in the biofilm, are administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In a further aspect, methods of treating a biofilm in a subject, comprise, or alternatively consist essentially of, or further consist of administering to the biofilm-infected subject an effective amount of three or more agents that interfere with polyamine binding. to DNA in the biofilm, which, in one aspect, are administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In yet another aspect, methods of treating a biofilm in a subject, comprise, or alternatively consist essentially of, or further consist of administering to the subject infected with a biofilm an effective amount of four or more, or alternatively five or more, or alternatively six or more, or alternatively seven or more, or alternatively eight or more, or alternatively nine or more, or alternatively ten or more agents that interfere with the binding of a polyamine to DNA in the biofilm, which, in one aspect, are administered in absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. This disclosure also relates to methods of preventing the formation of a biofilm in a subject susceptible to developing a biofilm, comprising, or alternatively consisting essentially of, or further consisting of administering to the subject an effective amount of an agent that interferes with the binding, of a polyamine to DNA in the biofilm, that in one aspect, where the agent is not an HMGB1 protein, a fragment or an equivalent of each, and in another aspect, the agent is administered in the absence of a DNase. In a further aspect, the DNase is administered after the Rcncrn / Lznza / YiAi agent management. In a particulate aspect, the DNase administered is Pulmozyme. In one aspect, methods of preventing the formation of a biofilm in a subject susceptible to developing a biofilm, comprising, or alternatively consisting essentially of, or further consisting of administering to the subject an effective amount of one or more agents that interfere with binding of a polyamine to DNA in the biofilm the agent is not an HMGB1 protein, a fragment or an equivalent of each, and in one aspect, the agent is administered in the absence of a DNase. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In another aspect, methods of preventing the formation of a biofilm in a subject susceptible to developing a biofilm, comprise, or alternatively consist essentially of, or further consist of administering to the subject an effective amount of two or more binding interfering agents. of a polyamine to the DNA in the biofilm, which in one aspect, are delivered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In a further aspect, methods of preventing the formation of a biofilm in a subject susceptible to developing a biofilm, comprise, or alternatively consist essentially of, or further consist of administering to the biofilm subject an effective amount of three or more interfering agents. with the binding of a polyamine to DNA in the biofilm, which, in one aspect, are administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In yet another aspect, methods of preventing the formation of a biofilm in a subject susceptible to developing a biofilm, comprise, or alternatively consist essentially of, or further consist of administering to the subject a biofilm in an effective amount of four or more, or alternatively five or more, or alternatively six or more, or alternatively seven or more, or alternatively eight or more, or alternatively nine or more, or alternatively ten or more agents that interfere with the binding of a polyamine to DNA in the biofilm, which in one aspect, they are administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. This disclosure further relates to methods of treating an infection caused by a biofilm-producing bacterium in a subject in need thereof, the method comprising, or alternatively consisting essentially of, or further consisting of administering to the subject an effective amount of a which interferes with the binding of a polyamine to DNA in the biofilm and an agent that inhibits the replication of the organism, which, in one aspect, is administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In one aspect, methods of treating an infection caused by a biofilm-producing bacterium in a subject in need thereof, the method comprises, or alternatively consists essentially of, or further consists of administering to the subject an effective amount of one or more agents that interfere with the binding of a polyamine to DNA in the biofilm. In another aspect, methods of treating an infection caused by a biofilm-producing bacterium in a subject in need thereof, the method comprises, or alternatively consists essentially of, or further consists of administering to the subject an effective amount of two or more agents that interfere with the binding of a polyamine to DNA in the biofilm and an agent that inhibits the replication of the organism. In one aspect, the agents are administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In a further aspect, methods of treating an infection caused by a biofilm-producing bacterium in a subject in need thereof, the method comprises, or alternatively consists essentially of, or further consists of administering to the subject an effective amount of three or plus agents that interfere with the binding of a polyamine to DNA in the biofilm and an agent that inhibits replication of the organism which, in one aspect, are administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In yet another aspect, methods of treating an infection caused by a biofilm-producing bacterium in a subject in need thereof, the method comprises, or alternatively consists essentially of, or further consists of administering to the subject a biofilm in an effective amount of four or more, or alternatively five or more, or alternatively six or more, or alternatively seven or more, or alternatively eight or more, or alternatively nine or more, or alternatively ten or more agents that interfere with the binding of a polyamine to DNA in the biofilm and an agent that inhibits the replication of the organism which, in one aspect, are administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after the Rcncrn / Lznza / YiAi agent management. In a particulate aspect, the DNase administered is Pulmozyme. For any of the methods described above, the polyamine can be selected from the group of: putrescine, spermine, cadaverine, 1,3-diaminopropane or spermidine. In one embodiment, for the methods described above, the agent that interferes with the binding of a polyamine to DNA in the biofilm is a tRNA. In another embodiment, the agent is a polyamine synthesis inhibitor or an agent that inhibits polyamine binding to DNA. In a second embodiment, the agent comprises, or alternatively consists essentially of, or even consists of a polyamine analogue difluoromethylornithine, trans-4-methylcyclohexylamine, sardomozide, methylglyoxal-bis[guanylhydrazone] (MGBG), 1-aminooxy-3-aminopropane, oxaliplatin , cisplatin, dicyclohexylamine, a derivative of any of them, or a salt thereof. In one aspect, derivatives of these compounds maintain the same mass / charge ratio. In a third embodiment, the agent comprises, or alternatively consists essentially of, or further consists of, a biofilm cation-depleting agent, optionally a cation exchange resin, an aminopolycarboxylic acid, a crown ether, an aza crown, or a cryptand. In a fourth embodiment, the biofilm cation-depleting agent is selected from the group of: sulfonate, sulfopropyl, phosphocellulose, P11 phosphocellulose, heparin sulfate, or a derivative or analogue thereof. In one aspect, a derivative or analog of the biofilm cation depleting agent is a resin having a net negative charge. In a fifth embodiment, the agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment. In a sixth embodiment, the agent comprises, or alternatively consists essentially of, or even further consists of an anti-DNA-B antibody or fragment or derivative thereof. In one aspect, the polyclonal or monoclonal anti-DNA-B antibody or fragment or derivative thereof recognizes B-form DNA over Z-form DNA by at least 10-fold affinity / avidity. In a seventh embodiment, the agent comprises, or alternatively consists essentially of, or further consists of riboflavin, ethidium bromide, bis(methidium)spermine, daunorubicin, TMPyP4, a quaternary benzo[c]phenanthridine alkaloid, quinacrine, 9- amino acridine, or a derivative thereof. In an eighth embodiment, the agent comprises, or alternatively consists essentially of, or even further consists of chloroquine or a derivative thereof. In one aspect, derivatives of the compounds retain the ability to intercalate between DNA bases. In one aspect, the agent is not an HGMB1 protein or fragment thereof. In one aspect, the biofilm cation-depleting agent has a net negative charge. In another aspect, the biofilm cation-depleting agent has a net neutral charge. Also provided herein are methods for treating a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF), who Rcncrn / Lznza / YiAi Rcncrn / Lznza / YiAi comprise, or alternatively consist essentially of, or further consist of administering an effective amount of an agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment that, in one aspect, is administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. Methods for treating a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF) and / or TB, comprising, or alternatively consisting essentially of, or additionally consisting of administering an effective amount of one or more agents that interfere with the conversion of B-DNA to Z-DNA in the biofilm or its local environment are described herein that, in one aspect, are administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In one aspect, methods for treating a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF) and / or TB, comprising, or alternatively essentially consisting of, or additionally consisting of administering An effective amount of two or more agents that interfere with the conversion of B-DNA to Z-DNA in the biofilm or its local environment are described herein that, in one aspect, are administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In another aspect, methods for treating a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF) and / or TB, comprising, or alternatively consisting essentially of, or additionally consisting of administering An effective amount of three or more agents that interfere with the conversion of B-DNA to Z-DNA in the biofilm or its local environment are described herein. In a further aspect, methods for treating a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF) and / or TB, comprising, or alternatively essentially consisting of, or additionally consisting of administer an effective amount of four or more, or alternatively five or more, or alternatively six or more, or alternatively seven or more, or alternatively eight or more, or alternatively nine or more, or alternatively ten or more conversion interfering agents of B-DNA to Z-DNA in the biofilm or its local environment are described herein that, in one aspect, are administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment or an equivalent of each of the Rcncrn / Lznza / YiAi themselves. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In one embodiment, the agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment. In a second embodiment, the agent comprises, or alternatively consists essentially of, or even further consists of an anti-DNA-B antibody or fragment or derivative thereof. In one aspect, the polyclonal or monoclonal anti-DNA-B antibody or fragment or derivative thereof recognizes B-form DNA over Z-form DNA by at least 10-fold affinity / avidity. In a third embodiment, the agent comprises, or alternatively consists essentially of, or further consists of riboflavin, ethidium bromide, bis(methidium)spermine, daunorubicin, TMPyP4, a quaternary benzo[c]phenanthridine alkaloid, quinacrine, 9- amino acridine, or a derivative thereof. In a further embodiment, the agent comprises, or alternatively consists essentially of, or even further consists of chloroquine or a derivative thereof. In one aspect, derivatives of the compounds retain the ability to intercalate between DNA bases. The agent is not an HGMB1 protein or a fragment thereof. Methods for treating a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF) and / or TB, comprising, or alternatively consisting essentially of, or further consisting of administering an effective amount of HMGB1 protein or a biologically active fragment thereof and anti-B-DNA antibody or fragment or derivative thereof are also provided herein which, in one aspect, are administered in the absence of a DNase. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In one aspect, the polyclonal or monoclonal anti-DNA-B antibody or fragment or derivative thereof recognizes B-form DNA over Z-form DNA by at least 10-fold affinity / avidity. The biologically active fragment of HMGB1 may comprise, or alternatively consist essentially of, or further consist of one or more of: an A-box, a B-box and / or an AB-box, a C-terminal fragment or an N-terminal fragment . In a specific embodiment, the biologically active fragment of HMGB1 may comprise, or alternatively consist essentially of, or further consist of the Box B domain that is capable of binding to DNA. In one aspect, the method for treating a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF) and / or TB, comprises, or alternatively consists essentially of, or further consists of administering an effective amount of chloroquine and the anti-DNA antibody or fragment or derivative thereof which, in one aspect, is administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after the Rcncrn / Lznza / YiAi agent management. In a particulate aspect, the DNase administered is Pulmozyme. This disclosure also relates to methods of treating an infection-producing biofilm related to the administration of a platinum-based chemotherapy in a patient receiving or has received the chemotherapy comprising, or alternatively essentially consisting of, or further consisting of administering an effective amount of an agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment which, in one aspect, is administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In one aspect, the method comprises, or alternatively consists essentially of, or even further consists of administering an effective amount of one or more agents that interfere with the conversion of B-DNA to Z-DNA in the biofilm or its local environment that, in one aspect, it is administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In a further aspect, the agent comprises, or alternatively consists essentially of, or even further consists of chloroquine or a derivative thereof. In yet a further embodiment, the agent comprises, or alternatively consists essentially of, or even further consists of an anti-DNA-B antibody or fragment or derivative thereof. In one aspect, the polyclonal or monoclonal anti-DNA-B antibody or fragment or derivative thereof recognizes B-form DNA over Z-form DNA by at least 10-fold affinity / avidity. In one embodiment, the agent comprises, or alternatively consists essentially of, or further consists of riboflavin, ethidium bromide, bis(methidium)spermine, daunorubicin, TMPyP4, a quaternary benzo[c]phenanthridine alkaloid, quinacrine, 9-amino acridine, or a derivative thereof. In a particular aspect, derivatives of the compounds retain the ability to intercalate between DNA bases. This disclosure further relates to methods of treating an infection-producing biofilm related to the administration of a platinum-based chemotherapy in a patient receiving or has received the chemotherapy comprising, or alternatively essentially consisting of, or further consisting of administering an effective amount of HMGB1 protein or biologically active fragment thereof which, in one aspect, is administered in the absence of a DNase. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In one aspect, the polyclonal or monoclonal anti-B-DNA antibody or fragment or derivative thereof recognizes B-form DNA over Z-form DNA at least 10-fold in Rcncrn / Lznza / YiAi affinity / greed. The biologically active fragment of HMGB1 may comprise, or alternatively consist essentially of, or further consist of one or more of: an A-box, a B-box and / or an AB-box, a C-terminal fragment or an N-terminal fragment . In a specific embodiment, the biologically active fragment of HMGB1 may comprise, or alternatively consist essentially of, or further consist of the Box B domain that is capable of binding to DNA. Also provided herein are methods of treating an infection-producing biofilm related to the administration of a platinum-based chemotherapy in a patient receiving or having received chemotherapy comprising, or alternatively consisting essentially of, or further consisting of administering an effective amount of chloroquine and anti-DNA-B antibody or fragment or derivative thereof which, in one aspect, are administered in the absence of a DNase. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In one aspect, the polyclonal or monoclonal anti-DNA-B antibody or fragment or derivative thereof recognizes B-form DNA over Z-form DNA by at least 10-fold affinity / avidity. The methods described above may further comprise, or alternatively consist essentially of, or further consist of administering to the subject, an effective amount of an agent that interferes with eDNA binding to a DNA-binding protein and / or an antibacterial agent that in one aspect it is administered in the absence of a DNase. In another aspect, the agent is not a HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In one aspect, the methods further comprise, or alternatively consist essentially of, or even further consist of administering to the subject an effective amount of an agent that interferes with eDNA binding to a DNA-binding protein and / or an antibacterial agent that , in one aspect, is administered in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particulate aspect, the DNase administered is Pulmozyme. In another aspect, the agent that interferes with the binding of eDNA to the DNA-binding protein comprises, or alternatively consists essentially of, or further consists of one or more of an anti-DNABII antibody, an anti-IHF antibody, and / or an anti-HU antibody, or fragments of each. In one embodiment, the agent that interferes with eDNA binding to a DNA binding protein has a net negative charge. In a second embodiment, the agent that interferes with eDNA binding to a DNA binding protein has a neutral negative charge. In a third embodiment, the agent that interferes with eDNA binding to a DNA binding protein has a net positive charge. Described herein are methods for inhibiting the stability of a biofilm, comprising, or alternatively consisting essentially of, or further consisting of contacting the biofilm with an effective amount of an agent that interferes with the binding of a polyamine to DNA. in the biofilm which, in one aspect, is contacted in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. In a particular aspect, methods for inhibiting the stability of a biofilm, which comprise, or alternatively consist essentially of, or further consist of contacting the biofilm with an effective amount of one or more agents that interfere with the binding of a biofilm. polyamine to DNA in the biofilm which, in one aspect, are contacted in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. In another aspect methods of inhibiting the stability of a biofilm comprise, or alternatively consist essentially of, or further consist of contacting the biofilm with an effective amount of two or more agents that interfere with the binding of a polyamine to DNA in the biofilm that, in one aspect, are contacted in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. In a further aspect, methods for inhibiting the stability of a biofilm comprise, or alternatively consist essentially of, or further consist of contacting the biofilm with an effective amount of three or more agents that interfere with the binding of a polyamine to the biofilm. DNA in the biofilm that, in one aspect, contacts in the absence of a DNase. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. In yet another aspect, methods for inhibiting the stability of a biofilm comprise, or alternatively consist essentially of, or further consist of contacting the biofilm with an effective amount of four or more, or alternatively five or more, or alternatively six or more, or alternatively seven or more, or alternatively eight or more, or alternatively nine or more, or alternatively ten or more agents that interfere with the binding of a polyamine to DNA in the biofilm, that in one aspect, contact in the absence of a DNase. In another aspect, the agent Rcncrn / Lznza / YiAi «cnccni znzq / YiAi is not an HMGB1 protein, fragment or equivalent thereof. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. The contact can be in vitro or in vivo. This disclosure also relates to methods of inhibiting the stability of a biofilm, which comprise, or alternatively consist essentially of, or further consist of contacting the biofilm in vitro with an agent that interferes with the binding of a polyamine to DNA in biofilm, wherein the contacting comprises, or alternatively consists essentially of, or even further consists of coating a surface with an effective amount of cation-depleting agent, which, in one aspect, is contacted in the absence of a DNase, while in another aspect, the DNase is contacted according to the method. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. In one aspect, methods for inhibiting the stability of a biofilm may comprise, or alternatively consist essentially of, or further consist of contacting the biofilm in vitro with an effective amount of an agent that interferes with polyamine DNA binding. in biofilm, wherein the contacting comprises, or alternatively consists essentially of, or further consists of coating a surface with an effective amount of one or more cation-depleting agents that, in one aspect, are contacted in the absence of of a DNase, while in another aspect, the DNase is contacted according to the method. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. In another aspect, methods for inhibiting the stability of a biofilm may comprise, or alternatively consist essentially of, or further consist of contacting the biofilm in vitro with an effective amount of an agent that interferes with polyamine DNA binding. in biofilm, wherein the contacting comprises, or alternatively consists essentially of, or further consists of coating a surface with an effective amount of two or more agents that are, in one aspect, contacted in the absence of a DNase, while in another aspect, the DNase is contacted according to the method. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. Rcncpn / Lznza / YiAi In a further aspect, methods for inhibiting the stability of a biofilm may comprise, or alternatively consist essentially of, or further consist of contacting the biofilm in vitro with an effective amount of an agent that interferes with polyamine binding. to DNA in the biofilm, wherein the contact comprises, or alternatively consists essentially of, or even further consists of coating a surface with an effective amount of three or more cation-depleting agents, which, in one aspect, contact in the absence of a DNase, while in another aspect, the DNase is contacted in accordance with the method. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. In yet another aspect, methods of inhibiting the stability of a biofilm may comprise, or alternatively consist essentially of, or further consist of contacting the biofilm in vitro with an effective amount of an agent that interferes with polyamine binding. DNA in the biofilm, wherein the contacting comprises, or alternatively consists essentially of, or further consists of coating a surface with an effective amount of four or more, or alternatively five or more, or alternatively six or more, or alternatively seven or more, or alternatively eight or more, or alternatively nine or more, or alternatively ten or more cation depleting agents. In one embodiment, the agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment which, in one aspect, are contacted in the absence of a DNase, while in another aspect, the DNase contacts according to the method. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. In a second embodiment, the agent comprises, or alternatively consists essentially of, or even further consists of an anti-DNA-B antibody or fragment or derivative thereof. In one aspect, the polyclonal or monoclonal anti-DNA-B antibody or fragment or derivative thereof recognizes B-form DNA over Z-form DNA by at least 10-fold affinity / avidity. In a third embodiment, the agent comprises, or alternatively consists essentially of, or further consists of riboflavin, ethidium bromide, bis(methidium)spermine, daunorubicin, TMPyP4, a quaternary benzo[c]phenanthridine alkaloid, quinacrine, 9-amino acridine, or a derivative thereof. In a fifth embodiment, the agent comprises, or alternatively consists essentially of, or even further consists of chloroquine or a derivative thereof. In a particular aspect, derivatives of the compounds retain the ability to intercalate between DNA bases. The agent is not an HGMB1 protein or a fragment thereof. Further described herein are methods for inhibiting the stability of a biofilm, which comprise, or alternatively consist essentially of, or further consist of contacting the biofilm in vitro with an effective amount of HMGB1 protein or biologically active fragment thereof. and anti-DNA-B antibody or fragment or derivative thereof, wherein the contacting comprises, or alternatively consists essentially of, or even further consists of coating a surface with an effective amount of HMGB1 protein or biologically active fragment thereof and antibody anti-DNA-B or fragment or derivative thereof which, in one aspect, is contacted in the absence of a DNase, while in another aspect, the DNase is contacted in accordance with the method. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. In one aspect, the polyclonal or monoclonal anti-DNA-B antibody or fragment or derivative thereof recognizes B-form DNA over Z-form DNA by at least 10-fold affinity / avidity. The biologically active fragment of HMGB1 may comprise, or alternatively consist essentially of, or further consist of one or more of: an A-box, an AB-box, a B-box, a C-terminal fragment and / or an N-terminal fragment . In a specific embodiment, the biologically active fragment of HMGB1 may comprise, or alternatively consist essentially of, or further consist of the Box B domain that is capable of binding to DNA. This disclosure also relates to methods of inhibiting the stability of a biofilm, which comprise, or alternatively consist essentially of, or further consist of contacting the biofilm in vitro with an effective amount of chloroquine and anti-DNA-B antibody or fragment or derivative thereof, wherein the contacting comprises, or alternatively consists essentially of, or further consists of coating a surface with an effective amount of chloroquine and anti-DNA-B antibody or fragment or derivative thereof which, in one aspect, contacted in the absence of a DNase. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. In one aspect, the polyclonal or monoclonal anti-DNA-B antibody or fragment or derivative thereof recognizes B-form DNA over Z-form DNA by at least 10-fold affinity / avidity. The methods described above may further comprise, or alternatively consist essentially of, or further consist of contacting the biofilm with an effective amount of an agent that interferes with eDNA binding to a DNA-binding protein and / or an agent. antibacterial which in one aspect is contacted in the absence of a DNase, while in another aspect, the DNase is contacted in accordance with the method. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. In Rcncrn / Lznza / YiAi Rcncrn / Lznza / YiAi In one aspect, the agent that interferes with the binding of eDNA to the DNA-binding protein comprises, or alternatively consists essentially of, or further consists of one or more of an anti-DNABII antibody, an anti-DNABII antibody, IHF and / or an anti-HU antibody, or fragments of each, which, in one aspect, are contacted in the absence of a DNase. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In one embodiment, the agent that interferes with eDNA binding to a DNA binding protein has a net negative charge which, in one aspect, contacts in the absence of a DNase. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. In a second embodiment, the agent that interferes with eDNA binding to a DNA-binding protein has a net neutral charge that, in one aspect, contacts in the absence of a DNase, while in another aspect, the DNase contacts according to the method. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. In a third embodiment, the agent that interferes with eDNA binding to a DNA binding protein has a net positive charge. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. Provided herein are methods of inhibiting the stability of a biofilm, comprising contacting the biofilm with an agent that interferes with the binding of a polyamine to DNA in the biofilm which, in one aspect, is contacted in the absence of a DNase, while in another aspect, the DNase is contacted according to the method. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is contacted after contacting the agent. In a particular aspect, the DNase is Pulmozyme. The contact can be in vitro or in vivo. Also provided are methods of treating a biofilm in a subject, comprising administering to the biofilm-infected subject an effective amount of an agent that interferes with the binding of a polyamine to DNA in the biofilm which, in one aspect, is administered in the in the absence of a DNase, while in another aspect, the DNase is administered. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particular aspect, the DNase is Pulmozyme. Further provided are methods of preventing the formation of a biofilm in a subject susceptible to developing a biofilm, comprising administering to the subject an effective amount of an agent that interferes with the binding of a polyamine to DNA in the biofilm that, in one aspect, it is administered in the absence of a DNase while in another aspect, the DNase is administered. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particular aspect, the DNase is Pulmozyme. Also provided are methods of treating an infection caused by a biofilm-producing bacterium in a subject in need thereof, the method comprising administering to the subject an effective amount of an agent that interferes with the binding of a polyamine to DNA in the biofilm and a agent that inhibits the replication of the organism which, in one aspect, is administered in the absence of a DNase while in another aspect, the DNase is administered. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particular aspect, the DNase is Pulmozyme. In one aspect, the agent is an inhibitor of polyamine synthesis or an agent that inhibits the binding of polyamine to DNA. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. Non-limiting examples of polyamine include: putrescine, spermine, cadaverine, 1,3-diaminopropane, or spermidine. In another aspect, the agent comprises a polyamine analogue, difluoromethylornithine, trans-4-methylcyclohexylamine, sardomozide (Boc Sciences), methylglyoxal-bis[guanylhydrazone] (methylGAG), 1-aminooxy-3-aminopropane (AKos Consulting & Solutions), oxaliplatin, cisplatin, dicyclohexylamine, a derivative thereof, or a salt thereof (all agents in this paragraph are commercially available from Millipore Sigma unless otherwise indicated). In one aspect, derivatives of these compounds maintain the same mass / charge ratio. In a further aspect, the agent comprises a biofilm cation depleting agent, optionally a cation exchange resin, an aminopolycarboxylic acid, a crown ether, an aza crown, or a cryptand (several representative compounds from each class of agent). available from Millipore Sigma). In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. Non-limiting examples of a cation exchange resin include sulfonate, sulfopropyl, phosphocellulose, P11 phosphocellulose, heparin sulfate, or resins containing a derivative or analog thereof. In one embodiment, the biofilm cation-depleting agent has a net negative charge. In one embodiment, the biofilm cation-depleting agent has a net neutral charge. Rcncrn / Lznza / YiAi Rcncrn / Lznza / YiAi In one embodiment, methods of inhibiting the stability of a biofilm are provided herein, comprising contacting the biofilm in vitro with an agent that interferes with the binding of a polyamine to DNA in the biofilm and the contacting comprises coating a surface with the cation-depleting agent being, in one aspect, administered in the absence of a DNase while, in another aspect, the DNase is administered. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particular aspect, the DNase is Pulmozyme. In one aspect of the above methods, the agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment which, in one aspect, is administered in the absence of a DNase while in another aspect, is administer DNase. In a further aspect, the DNase is administered after administration of the agent. In a particular aspect, the DNase is Pulmozyme. Examples of such include an anti-DNA-B antibody or a fragment or derivative thereof. In a further aspect, the agent comprises an agent from the group of: riboflavin, ethidium bromide, bis(methidium) spermine, (Dervan et al. (1978) 100(6):1968-1970) daunorubicin, TMPyP4, an alkaloid of quaternary benzo[c]phenanthridine, (Rajecky et al. (2015); Le et al. (2004) 69(8):2768-2772) quinacrine, 9-amino acridine or a derivative thereof (all agents in this additional aspect are commercially available from Millipore Sigma unless otherwise noted). The agent is not an HGMB1 protein or a fragment thereof. Further provided are methods of treating a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF), comprising administering an effective amount of an agent that interferes with the conversion of B-DNA to B-DNA Z in the biofilm or its local environment which, in one aspect, is administered in the absence of a DNase, while in another aspect, the DNase is administered. In a further aspect, the DNase is administered after administration of the agent. In a particular aspect, the DNase is Pulmozyme. Examples of such include anti-DNA-B antibody or a fragment or derivative thereof. In a further aspect, the agent comprises an agent from the group of: riboflavin, ethidium bromide, bis(methidio)spermine, daunorubicin, TMPyP4, a quaternary benzo[c]phenanthridine alkaloid, quinacrine, 9-amino acridine or a derivative thereof. In one aspect, the method is performed in the absence of a DNase, and in one aspect, CF treatment is performed in the absence of a DNase. The agent is not an HGMB1 protein or a fragment thereof. In another aspect, provided herein are methods for treating an infection-producing biofilm related to the administration of a platinum-based chemotherapy in a patient receiving or having received the chemotherapy, the method comprising Rcncrn / Lznza / YiAi administer an effective amount of an agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment that, in one aspect, is administered in the absence of a DNAase while in another aspect, it is administer DNAase. In a further aspect, the DNase is administered after administration of the agent. In a particular aspect, the DNase is Pulmozyme. Examples of such include an anti-DNA-B antibody or a fragment or derivative thereof. In a further aspect, the agent comprises an agent from the group of: riboflavin, ethidium bromide, bis(methidio)spermine, daunorubicin, TMPyP4, a quaternary benzo[c]phenanthridine alkaloid, quinacrine, 9-amino acridine or a derivative thereof. The agent is not an HGMB1 protein or a fragment thereof. The methods noted above may further comprise contacting the biofilm (when in vitro) or administering to the subject an effective amount of an agent that interferes with eDNA binding to a DNA-binding protein and / or an antibacterial agent that, in one aspect, it is administered in the absence of a DNase while in another aspect, the DNase is administered. In another aspect, the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. In a further aspect, the DNase is administered after administration of the agent. In a particular aspect, the DNase is Pulmozyme. In one embodiment, the agent that interferes with eDNA binding to a DNA binding protein has a net positive charge. In one embodiment, the agent that interferes with eDNA binding to a DNA binding protein has a net negative charge. In one embodiment, the agent that interferes with eDNA binding to a DNA binding protein has a net neutral charge. When practiced in vitro, the methods are useful for selecting or confirming agents that have the same, similar, or opposite capacity as the polypeptides, polynucleotides, antibodies, host cells, small molecules, and compositions described herein. Alternatively, they can be used to identify which agent is best suited to treat a microbial infection or whether the treatment has been effective. For example, new agents or combination therapies can be selected by having two samples containing, for example, DNABII polypeptide and microbial DNA and the agent to be tested. The second sample contains the DNABII polypeptide and microbial DNA and an agent known to be activated, eg, an anti-IHF antibody or small molecule to serve as a positive control. In a further aspect, various samples are provided and agents are added to the system in increasing dilutions to determine the optimal dose that would likely be effective in treating a subject in the clinical setting. As is apparent to those skilled in the art, a negative control containing DNABII polypeptide and microbial DNA can be provided. In a further aspect, DNABII polypeptide and microbial DNA are detectably labeled, for example, with luminescent molecules that Rcncrn / Lznza / YiAi will emit a signal when they come in close contact with each other. Samples are contained under similar conditions for a period of time effective for the agent to inhibit, compete, or titrate the interaction between DNABII polypeptide and microbial DNA, and then the sample is analyzed for signal emission from the luminescent molecules. If the sample emits a signal, then the agent is not effective in inhibiting binding. In another aspect, the in vitro method is practiced in a miniaturized chamber slide system in which the microbial isolate (such as a bacterium) causing an infection could be isolated from the human / animal and then cultured to allow it to grow as a biofilm. in vitro. The agent (such as an anti-DNABII or IHF antibody) or a test or potential agent is added alone or in combination with another agent to the culture with or without increasing dilutions of the agent or potential agent such as an anti-DNABII or IHF (or other antibody, small molecule, agent, etc.) to find the optimal dose that would likely be effective in treating that patient when administered to the subject where the infection existed. As is apparent to those skilled in the art, a positive and negative control can be run simultaneously. In a further aspect, the method is practiced on a high throughput platform with the agent (such as anti-DNABII antibody or IHF) and / or potential agent (alone or in combination with another agent) in a flow cell. The agent (such as an anti-DNABII or IHF antibody) or potential agent biofilm is added alone or in combination with another agent to the culture with or without increasing dilutions of the agent or potential agent such as an anti-DNABII or IHF (or other antibody, small molecule, agent, etc.) to find the optimal dose that would likely be effective in treating that patient when administered to the subject where the infection existed. Biofilm isolates are sonicated to separate the biofilm bacteria from DNABII polypeptide, such as IHF, bound to the microbial DNA. DNABII polypeptide-DNA complexes are isolated by virtue of anti-DNABII antibody or IHF on the platform. The microbial DNA is then released with, for example, a salt wash and used to identify the added biofilm bacteria. The released DNA is then identified, for example, by PCR sequencing. If the DNA is not released, then the agent(s) successfully carried out or bound the microbial DNA. If DNA is found in the sample, then the agent did not interfere with DNABII polypeptide-microbial DNA binding. As is apparent to those skilled in the art, a positive and / or negative control can be performed simultaneously. The above methods can also be used as a diagnostic test, as it is possible that a certain bacterial species is more responsive to biofilm reversal by one agent than another, this high throughput rapid assay system could allow an expert in the technique to analyze a panel of possible anti-DNABII agents or Rcncrn / Lznza / YiAi similar to IHF to identify the most effective of the group. The advantage of these methods is that most clinical microbiology laboratories in hospitals are already equipped to perform this type of assay (i.e. determination of MIC, CBM values) using bacteria grown in liquid culture (or planktonically). . As is apparent to those skilled in the art, bacteria generally do not develop a planktonic ally when they are causing disease. Instead, they are growing as a stable biofilm, and these biofilms are significantly more resistant to treatment with antibiotics, antibodies, or other therapies. This resistance is the reason why most MIC / MBC values ​​fail to accurately predict efficacy in vivo. Therefore, by determining what dose of agent could reverse a bacterial biofilm in vitro (as described above), applicants' preclinical assay would be a more reliable predictor of clinical efficacy, even as a personalized medicine application. In addition to the clinical setting, the methods can be used to identify the microbe causing the infection and / or confirm effective agents in an industrial setting. Thus, the agents can be used to treat, inhibit, or titrate a biofilm in an industrial setting. In a further aspect of the above methods, an antibiotic or antimicrobial known to inhibit the growth of the underlying infection is added sequentially or simultaneously, to determine if the infection can be inhibited. It is also possible to add the agent to microbial DNA or DNABII polypeptide before adding the missing complex to test for biofilm inhibition. When practiced in vivo in a non-human animal, such as a chinchilla, the method provides a preclinical screen to identify agents that can be used alone or in combination with other agents to break down biofilms. In another aspect, provided herein is a method of inhibiting, preventing, or disrupting a biofilm in a subject by administering to the subject an effective amount of an agent, thereby inhibiting, preventing, or disrupting the microbial biofilm. Non-limiting examples of such subjects include mammals, eg, pets, and human patients. The agents and compositions described herein may be administered simultaneously or sequentially with other antimicrobial agents and / or surface antigens. In a particular aspect, administration is locally to the site of infection by direct injection or by inhalation, for example. Other non-limiting examples of administration include one or more methods comprising transdermal, urethral, ​​sublingual, rectal, vaginal, ocular, subcutaneous, intramuscular, intraperitoneal, intranasal, inhalative, or oral. Microbial infections and diseases that can be treated by the methods described herein include infection by the organisms Streptococcus agalactiae, Rcncrn / Lznza / YiAi Neisseria meningitidis, Treponemes, denticola, pallidum, Burkholderia cepacia, or Burkholderia pseudomallei. In one aspect, the microbial infection is one or more of Haemophilus influenzae (nontypeable), Moraxella catarrhalis, Streptococcus pneumoniae, Streptococcus pyogenes, Pseudomonas aeruginosa, Mycobacterium tuberculosis. These microbial infections can be present in the upper, middle and lower respiratory tract (otitis, sinusitis, bronchitis, but also exacerbations of chronic obstructive pulmonary disease (COPD), chronic cough, complications and / or primary cause of cystic fibrosis (CF). and Acquired Pneumonia (CAP).Thus, by practicing the in vivo methods described herein, these diseases and complications of these infections can also be prevented or treated. Infections can also occur in the oral cavity (caries, periodontitis) and caused by Streptococcus mutans, Porphyromonas gingivalis, Aggregatibacter actinomvctemcomitans. Infections can also be localized to the skin (abscesses, staphylococcal infections, impetigo, secondary burn infection, Lyme disease) and caused by Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa and Borrelia burdorferi. Urinary tract infections (UTIs) can also be treated and are usually caused by Escherichia coli. Gastrointestinal (GI) tract infections (diarrhea, cholera, gallstones, gastric ulcers) are usually caused by Salmonella enterica serovar, Vibrio cholerae, and Helicobacter pylori. Genital tract infections include and are often caused by Neisseria gonorrhoeae. Infections can be from the bladder or from an indwelling device caused by Enterococcus faecalis. Infections associated with implanted prosthetic devices, such as artificial hip or knee replacements, or dental implants, or medical devices such as pumps, catheters, stents, or monitoring systems, typically caused by a variety of bacteria, can be treated by the methods described. in this document. These devices can be coated or conjugated with an agent as described herein. Therefore, by practicing the in vivo methods described herein, these diseases and complications of these infections can also be prevented or treated. Infections caused by Streptococcus agalactiae can also be treated by the methods described in this document and is the leading cause of bacterial sepsis in newborns. Infections caused by Neisseria meningitidis that can cause meningitis can also be treated. Thus, routes of administration applicable to the methods described herein include intranasal, intramuscular, urethral, ​​intratracheal, subcutaneous, intradermal, transdermal, topical, intravenous, rectal, nasal, oral, inhalation, and other routes of administration. enteral and parenteral. Routes of administration can be combined, if Rcncrn / Lznza / YiAi desired, or adjusted depending on the agent and / or effect desired. An active agent can be administered in a single dose or in multiple doses. Modalities of these methods and suitable routes for administration include systemic or localized routes. In general, suitable routes of administration for the methods described herein include, but are not limited to, direct injection, enteral, parenteral, or inhalation routes. Parenteral routes of administration other than inhalation administration include, but are not limited to, topical, transdermal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, and intravenous routes, i.e., any route of administration other than that of the digestive tube. Parenteral administration can be performed to effect systemic or local administration of the inhibitory agent. When systemic administration is desired, administration usually involves invasive or systemically absorbed topical or mucosal administration of pharmaceutical preparations. The agents described herein can also be administered to the subject via enteral administration. Enteral routes of administration include, but are not limited to, oral and rectal administration (eg, using a suppository). Methods of administration of the active through the skin or mucosa include, but are not limited to, topical application of a suitable pharmaceutical preparation, transcutaneous delivery, transdermal delivery, injection, and epidermal administration. For transdermal transmission, uptake enhancers or iontophoresis are suitable methods. Iontophoretic transmission can be achieved using commercially available patches that deliver their product continuously via electrical pulses through intact skin for periods of several days or longer. In various embodiments of the methods described herein, the agent is administered by inhalation, injection, or orally continuously, daily, at least once a day (QD), and in various embodiments two (BID), three ( TID) or even four times a day. Typically, the therapeutically effective daily dose may be at least about 1 mg, or at least about 10 mg, or at least about 100 mg, or about 200 to about 500 mg, and sometimes, depending on the compound, up to as much as about 1g to about 2.5g. Dosing can be accomplished according to the methods described herein using capsules, tablets, oral suspension, suspension for intramuscular injection, suspension for intravenous infusion, gel or cream for topical application, or suspension for intra-articular injection. The dosage, toxicity, and therapeutic efficacy of the compositions described herein can be determined by standard pharmaceutical procedures in cell culture or experimental animals, for example, to determine the LD50 (the lethal dose Rcncrn / Lznza / YiAi for 50% of the population) and the ED50 (the therapeutically effective dose in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the LD50 / ED50 ratio. In certain embodiments, the compositions exhibit high therapeutic indices. Although compounds that exhibit toxic side effects can be used, care must be taken when designing a delivery system that directs such compounds to the affected tissue site to minimize potential damage to uninfected cells and thus reduce side effects. secondary. Data obtained from cell culture assays and animal studies can be used to formulate a dosage range for use in humans. The dosage of such compounds is (in certain embodiments) within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration used. For any compound used in the methods, the therapeutically effective dose can be initially estimated from cell culture assays.A dose can be formulated in animal models to achieve a concentration range in circulating plasma that includes the IC50 (i.e., the concentration of test compound that achieves mean maximal symptom inhibition) as determined in cell culture Such information can be used to more accurately determine useful doses in humans Plasma levels can be measured, for example, by high performance liquid chromatography. In some embodiments, an effective amount of a composition sufficient to achieve a therapeutic or prophylactic effect, ranges from about 0.000001 mg per kilogram of body weight per administration to about 10,000 mg per kilogram of body weight per administration. Suitably, dosage ranges are from about 0.0001 mg per kilogram of body weight per administration to about 100 mg per kilogram of body weight per administration. Administration can be given as an initial dose, followed by one or more booster doses. Booster doses can be given one day, two days, three days, one week, two weeks, three weeks, one, two, three, six, or twelve months after an initial dose. In some embodiments, a booster dose is administered after an assessment of the subject's response to prior administrations. One of skill in the art will appreciate that certain factors may influence the dosage and time required to effectively treat a subject, including, but not limited to, the severity of the disease or disorder, previous treatments, general health, and / or age. of the subject, and other diseases present. In addition, treatment of a subject with a therapeutically effective amount of the therapeutic compositions described herein Rcncrn / Lznza / YiAi may include a single treatment or a series of treatments. Antibodies and derivatives thereof This disclosure also provides an antibody that specifically binds and / or recognizes and binds B DNA for use in the methods described herein. The antibody can be any of the various antibodies described herein, without limitation, examples of which include a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a human antibody, a coated antibody, a diabody, a humanized antibody, a antibody derivative, a recombinant humanized antibody, or a derivative or fragment of each. In one aspect, the fragment comprises, or alternatively consists essentially of, or even further consists of the CDR of the antibody. In one aspect, the antibody is detectably labeled or further comprises a detectable label conjugated thereto. Also provided is a hybridoma cell line that produces a monoclonal antibody described herein. Compositions comprising or alternatively consisting essentially of or even more, consisting of one or more of the above embodiments are further provided herein. Further provided are polynucleotides encoding the amino acid sequence of the antibodies and fragments as well as methods for recombinantly producing or chemically synthesizing the antibody polypeptides and fragments thereof. Antibody polypeptides can be produced in a eukaryotic or prokaryotic cell, or by other methods known in the art and described herein. Variations on this methodology include modification of adjuvants, routes and site of administration, injection volumes per site, and number of sites per animal for optimal production and humane treatment of the animal. For example, adjuvants are typically used to enhance or enhance an immune response to antigens. Most adjuvants provide a reservoir of antigen at the injection site, allowing release of antigen into draining lymph nodes. Other adjuvants include surfactants that promote the concentration of protein antigen molecules over a large surface area and immunostimulatory molecules. Non-limiting examples of adjuvants for the generation of polyclonal antibodies include Freund's adjuvants, Ribi adjuvant system, and Titermax. Polyclonal antibodies can be generated using methods known in the art, some of which are described in US Patent Nos. 7,279,559; 7,119,179; 7,060,800; 6,709,659; 6,656,746; 6,322,788; 5,686,073; and 5,670,153. Monoclonal antibodies can be generated using standard hybridoma techniques known in the art and well described in the literature. For example, a hybridoma is produced by fusing a suitable immortal cell line (for example, a line Rcncrn / Lznza / YiAi myeloma cell such as, but not limited to, Sp2 / 0, Sp2 / 0-AG14, NSO, NS1, NS2, AE-1, L.5, P3X63Ag8,653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5, U397, MIA 144, ACT IV, MOLT4, DA-1, JURKAT, WEHI, K-562, COS, RAJI, NIH 313, HL-60, MLA 144, NAMAIWA, NEURO 2A, CHO, PerC .6, YB2 / O) or the like, or heteromyelomas, fusion products thereof, or any cells or fusion cells derived therefrom, or any other suitable cell lines as known in the art (see those found in the following web addresses, eg, atcc.org, lifetech.com, last accessed November 26, 2007), with antibody-producing cells, such as, but not limited to, isolated or cloned spleen, peripheral blood, lymph, tonsils or other immune or B cell-containing cells, or any other cells expressing heavy or light chain constant or variable CDR sequences, whether as endogenous or heterologous nucleic acid, as recombinant or endogenous, viral, bacterial, algal, prokaryote, amphibian, insect, reptile, fish, mammal, rodent, equine, sheep, caprine, ovine, primate, eukaryote, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hRNA, mRNA, tRNA, single-stranded, double-stranded or triple-stranded, annealed and the like or any combination thereof. Antibody-producing cells may also be obtained from peripheral blood or, in particular embodiments, spleen or lymph nodes, from humans or other suitable animals that have been immunized with the antigen of interest and then screened for activity of antibodies. interest. Any other suitable host cell may also be used to express endogenous or heterologous nucleic acid encoding an antibody, specified fragment or variant thereof, of the present disclosure. Fused cells (hybridomas) or recombinant cells may be isolated using selective culture conditions or other suitable known methods, and cloned by limiting dilution or cell sorting or other known methods. Other suitable methods for producing or isolating antibodies of the required specificity may be used, including, but not limited to, methods that select for a recombinant antibody from a peptide or protein library (for example, but not limited to, a bacteriophage, ribosome, oligonucleotide, cDNA or similar, presentation library, eg available from various commercial vendors such as MorphoSys (Martinsreid / Planegg, Delaware), Biolnvent (Lund, Sweden), Affitech (Oslo, Norway) using methods known in the art. in the art are described in the patent literature, some of which include US Patent Nos. 4,704,692, 5,723,323, 5,763,192, 5,814,476, 5,817,483, 5,824,514, and 5,976,862.Alternative methods are based on immunization of transgenic animals. (eg SCID mice, Nguyen et al. (1977) Microbiol. Immunol. 41:901-907 (1997); Sandhu et al. (1996) Crit, Rev. Biotechnol. 16:95-118; Eren et al. (1998) Mumma 93:154-161 that are capable of producing a repertoire of human antibodies, as known in the art and / or as described herein. Rcncrn / Lznza / YiAi Such techniques include, but are not limited to, ribosome display Wanes et al. (1997) Proc. nati. Acad. Sci. USA 94:4937-4942; Kanes et al. (1998) Proc. nati. Acad. Sci. USA 95:14130-14135); single cell antibody production technologies (eg, Selected Lymphocyte Antibody Method (SLAM)) (US Patent No. 5,627,052; Wen et al. (1987) J. Immunol 17:887-892; Babcook et al. (1996) Proc. Nati. Acad. Sci. USA 93:78437848), gel beads and flow cytometry (Powell et al. (1990) Biotechnol. 8:333-337; One Cell Systems, (Cambridge, Mass.) Grayet et al. (1995) J. Imm. Meth. 182:155-163; and Kenny et al. (1995) Bio. Technol. 13:787-790), T cell selection (Steenbakkers et al. (1994) Molec Biol. Reports 19:125-134). The antibody derivatives of the present disclosure may also be prepared by administering a polynucleotide encoding an antibody described herein to a suitable host to provide transgenic animals or mammals, such as goats, cows, horses, sheep, and the like, that produce these antibodies in your milk. These methods are known in the art and are described, for example, in US Patent Nos. 5,827,690; 5,849,992; 4,873,316; 5,849,992; 5,994,616; 5,565,362; and 5,304,489. The term "antibody derivative" includes the post-translational modification of the linear polypeptide sequence of the antibody or fragment. For example, US Patent No. 6,602,684 B1 describes a method for the generation of glycol-modified antibodies, including complete antibody molecules, antibody fragments, or fusion proteins that include a region equivalent to the region Fe of an immunoglobulin, having enhanced Fe-mediated cellular toxicity, and glycoproteins thus generated. The antibodies described herein also include derivatives that are modified by the covalent attachment of any type of molecule to the antibody such that the covalent attachment does not prevent the antibody from generating an anti-idiotypic response. Antibody derivatives include, but are not limited to, antibodies that have been modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, binding to a cellular ligand or other protein, etc. Furthermore, the derivatives may contain one or more non-classical amino acids. Antibody derivatives can also be prepared by administering a polynucleotide described herein to provide transgenic plants and cultured plant cells (for example, but not limited to tobacco, corn, and duckweed) that produce such antibodies, portions, or variants specified in the plant parts or in cells grown from them. For example, Cramer et al. (1999) Curr. Top. Microbol. Immunol. 240:95-118 and the references cited therein, describe the production of transgenic tobacco leaves that express large amounts of recombinant proteins, for example, Rcncrn / Lznza / YiAi using an inducible promoter. Transgenic maize has been used to express mammalian proteins at commercial production levels, with biological activities equivalent to those produced in other recombinant systems or purified from natural sources. See, for example, Hood et al. (1999) Adv. Exp. Med. Biol. 464:127-147 and references cited therein. Antibody derivatives have also been produced in large quantities from the seeds of transgenic plants, including antibody fragments, such as single chain antibodies (scFv), including tobacco seeds and potato tubers. See, for example, Conrad et al. (1998) Plant Mol. Biol. 38:101-109 and references cited there. Therefore, antibodies can also be produced using transgenic plants, according to known methods. Antibody derivatives may also be produced, for example, by adding exogenous sequences to modify immunogenicity or to reduce, enhance, or modify binding, affinity, active rate, inactive rate, avidity, specificity, half-life, or any other suitable characteristic. Generally, some or all of the non-human or human CDR sequences are retained while the non-human variable and constant region sequences are replaced with human amino acids or other amino acids or variable or constant regions of other isotypes. In general, CDR residues are directly and substantially involved in influencing antigen binding. The humanization or engineering of antibodies can be performed using any known method such as, but not limited to, those described in US Patent Nos. 5,723,323; 5,976,862; 5,824,514; 5,817,483; 5,814,476; 5,763,192; 5,723,323; 5,766,886; 5,714,352; 6,204,023; 6,180,370; 5,693,762; 5,530,101; 5,585,089; 5,225,539; and 4,816,567. Chimeric, humanized, or primatized antibodies of the present disclosure can be prepared based on the sequence of a reference monoclonal antibody prepared using standard molecular biology techniques. DNA encoding the heavy and light chain immunoglobulins can be obtained from the hybridoma of interest and modified to contain non-reference (eg, human) immunoglobulin sequences using standard molecular biology techniques. For example, to create a chimeric antibody, murine variable regions can be linked to human constant regions using methods known in the art (US Patent No. 4,816,567). To create a humanized antibody, murine CDR regions can be inserted into a human WORKFRAME using methods known in the art (US Patent No. 5,225,539 and US Patent Nos. 5,530,101; 5,585,089; 5,693,762; and 6,180,370). Similarly, to create a primatized antibody, murine CDR regions can be inserted into a primate framework using methods known in the art (WO 93 / 02108 and WO 99 / 55369). Techniques for making antibodies partially or Rcncrn / Lznza / YiAi are fully human and any such technique can be used. According to one embodiment, fully human antibody sequences are prepared in a transgenic mouse that has been engineered to express human heavy and light chain antibody genes. Multiple strains of such transgenic mice have been made that can produce different classes of antibodies. B cells from transgenic mice that are producing a desirable antibody can be fused to form hybridoma cell lines for continued production of the desired antibody. (See for example, Russel et al. (2000) Infection and Immunity April 2000:1820-1826; Gallo et al. (2000) European J. of Immun. 30:534-540; Green (1999) J. of Immun. Methods 231:11-23, Yang et al (1999A) J. of Leukocyte Biology 66:401-410, Yang (1999B) Cancer Research 59(6):1236-1243, Jakobovits (1998) Advanced Drug Reviews 31:33 -42, Green and Jakobovits (1998) J Exp Med 188(3):483-495, Jakobovits (1998) Exp Opin Invest Drugs 7(4):607-614, Tsuda et al (1997) Genomics 42:413421, Sherman-Gold (1997) Genetic Engineering News 17(14), Mendez et al (1997) Nature Genetics 15:146-156, Jakobovits (1996) Weir's Handbook of Experimental Immunology, The Integrated Immune System Vol. IV, 194.1-194.7, Jakobovits (1995) Current Opinion in Biotechnology 6:561-566, Mendez et al (1995) Genomics 26:294-307, Jakobovits (1994) Current Biology 4(8):761-763, Arbones et al (1994) Immunity 1(4):247-260 Jakobovits (1993) Nature 362(6417):255-258 Jakobovits et al (1993) Proc Nati Acad Sci USA 90(6):2551 -2555; and US Patent No. 6,075,181.) The antibodies described herein can also be modified to create chimeric antibodies. Chimeric antibodies are those in which the various heavy and light chain domains of the antibodies are encoded by DNA from more than one species. See, for example, US Patent No. 4,816,567. Alternatively, the antibodies described herein can also be modified to create coated antibodies. Masked antibodies are those in which the outer amino acid residues of the antibody from one species are judiciously replaced or masked with those from a second species such that antibodies from the first species are not immunogenic in the second species, thereby reducing the antibody immunogenicity. Since the antigenicity of a protein depends primarily on the nature of its surface, the immunogenicity of an antibody could be reduced by replacing exposed residues that differ from those commonly found in antibodies from another mammalian species. This judicious substitution of outer residues should have little or no effect on inner domains or inter-domain contacts. Therefore, ligand binding properties should not be affected as a consequence of alterations that are confined to framework residues of the variable region. The process is known as masking, since only Rcncrn / Lznza / YiAi alters the outer surface or skin of the antibody, the supporting residues remain intact. The masking procedure makes use of the available sequence data for human antibody variable domains compiled by Kabat et al. (1987) Sequences of Proteins of Immunological interest, 4th ed., Bethesda, Md., National Institutes of Health, updates to this database and other accessible US and foreign databases (both nucleic acid and protein). Non-limiting examples of methods used to generate masked antibodies include EP 519596; US Patent No. 6,797,492; and are described in Padlan et al. (1991) Mol. Immunol. 28(4-5):489-498. The term antibody derivative also includes diabodies which are small antibody fragments with two antigen-binding sites, where the fragments comprise a heavy chain variable domain (VH) linked to a light chain variable domain (VL) on the same chain. polypeptide. (See, for example, EP 404,097; WO 93 / 11161; and Hollinger et al. (1993) Proc. Nati. Acad. Sci. USA 90:6444-6448.) Using a ligator that is too short to allow pairing between the two domains on the same strand, the domains are forced to pair with the complementary domains of another strand and create two antigen-binding sites. (See also, US Patent No. 6,632,926 to Chen et al., which describes antibody variants that have one or more amino acids inserted into a hypervariable region of the original antibody and a binding affinity for a target antigen that is at least least about twice as strong as the original antibody's binding affinity for the antigen). The term antibody derivative further includes genetically modified individual antibody molecules, fragments and domains such as scFv, dAbs, nanobodies, minibodies, Unibodies and Affibodies & Hudson (2005) Nature Biotech 23(9):1126-36; US Patent Application Publication 2006 / 0211088; PCT, International Application Publication No. WO 2007 / 059782; US Patent No. 5,831,012). The term "antibody derivative" further includes linear antibodies. The procedure for making linear antibodies is known in the art and is described in Zapata et al. (1995) Protein Eng. 8(10):1057-1062. Briefly, these antibodies comprise a pair of tandem Ed segments (Vh-Ch1-VH-Ch1) that form a pair of antigen-binding regions. Linear antibodies can be bispecific or monospecific. The antibodies described herein can be recovered and purified from recombinant cell cultures by known methods including, but not limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography chromatography, chromatography Rcncpn / Ι707 3 / ΥΙΛΙ for hydroxyapatite and lectin chromatography. High performance liquid chromatography (HPLC) can also be used for purification. Antibodies of the present disclosure include naturally purified products, products of chemical synthesis procedures, and products produced by recombinant techniques from a eukaryotic host, including, for example, yeast, higher plants, insect and mammalian cells, or alternatively from a prokaryotic host as described above. Various antibody production systems are described in Birch & Radner (2006) Adv. Drug Delivery Rev. 58: 671-685. If an antibody being tested binds to a protein or polypeptide, then the antibody being tested and the antibodies provided by this disclosure are equivalent. It is also possible to determine without undue experimentation whether an antibody has the same specificity as the antibody described herein by determining whether the antibody being tested prevents an antibody described herein from binding to the protein or polypeptide with which the antibody normally binds. it is reactive. If the antibody being tested competes with the antibody described herein as shown by decreased binding of the monoclonal antibody described herein, then it is likely that the two antibodies are binding to the same or a closely related epitope. Alternatively, one can pre-incubate the antibody described herein with a protein with which it normally reacts and determine if the antibody being tested has inhibition in its ability to bind antigen. If the antibody being tested is inhibited, then, in all likelihood, it has the same or closely related epitopic specificity as the antibody described herein. The term "antibody" is also intended to include antibodies to all immunoglobulin isotypes and subclasses. Particular isotypes of a monoclonal antibody can be prepared directly by selection of an initial fusion, or prepared secondarily, from a parental hybridoma secreting a monoclonal antibody of a different isotype by using the sibling selection technique to isolate class switch variants using the procedure described in Steplewski et al. (1985) Proc. nati. Acad. Sci. USA 82:8653 or Spira et al. (1984) J. ImmunoL Methods 74:307. Alternatively, recombinant DNA techniques can be used. Isolation of other monoclonal antibodies with the specificity of the monoclonal antibodies described herein can also be performed by one skilled in the art by producing anti-idiotypic antibodies. Herlin et al. (1986) Science 232:100. An anti-idiotypic antibody is an antibody that recognizes unique determinants present on the monoclonal antibody of interest. In some aspects described herein, it is useful to detectably or therapeutically label the antibody. Suitable labels are described supra. Methods for conjugating antibodies to these agents are known in the art. For purposes of illustration only, antibodies may be labeled with a detectable moiety such as a radioactive atom, a chromophore, a fluorophore, or the like. Such labeled antibodies can be used for diagnostic techniques, either in vivo or in a single test sample. The coupling of antibodies to low molecular weight haptens can increase the sensitivity of the antibody in an assay. The haptens can then be specifically detected by a second reaction. For example, it is common to use haptens such as biotin, which reacts with avidin, or dinitrophenol, pyridoxal, and fluorescein, which can react with specific anti-hapten antibodies. See, Harlow and Lane (1988) supra. The variable region of the antibodies of the present disclosure may be modified by mutating amino acid residues within the VH and / or VL CDR 1, CDR 2, and / or CDR 3 regions to improve one or more binding properties (eg, affinity) of the antibody. antibody. Mutations can be introduced by site-directed mutagenesis or PCR-mediated mutagenesis and the effect on antibody binding, or other functional property of interest, can be assessed in appropriate in vitro or in vivo assays. In certain embodiments, conservative modifications are introduced and typically no more than one, two, three, four, or five residues within a CDR region are altered. Mutations can be amino acid substitutions, additions, or deletions. Framework modifications can be made to antibodies to decrease immunogenicity, for example, by backmutating one or more framework residues to the corresponding germline sequence. In addition, the antibodies described herein can be designed to include modifications within the Fe region to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fe receptor binding, and / or antigen-dependent cellular cytotoxicity. Such modifications include, but are not limited to, alterations of the number of cisternae residues in the hinge region to facilitate heavy and light chain assembly or to increase or decrease antibody stability (US Patent No. 5,677,425) and amino acid mutations in the Fe hinge region to decrease the biological half-life of the antibody (US Patent No. 6,165,745). In addition, the antibodies described herein can be chemically modified. The glycosylation of an antibody can be altered, for example, by modifying one or more glycosylation sites within the antibody sequence to increase the affinity of the antibody for the antigen (US Patent Nos. 5,714,350 and 6,350,861). Alternatively, to increase antibody-dependent cell-mediated cytotoxicity, one can Rcncpn / Lznza / YiAi Rcncrn / Lznza / YiAi obtain a hypofucosylated antibody that has reduced amounts of fucosyl residues or an antibody that has increased bisecting GIcNac structures by expressing the antibody in a host cell with altered glycosylation mechanism (Shields, R. L. et al. (2002) J Biol. Chem. 277:26733-26740; Umana et al. (1999) Nat. Biotech. 17:176-180). The antibodies described herein can be pegylated to increase the biological half-life by reacting the antibody or fragment thereof with polyethylene glycol (PEG) or a reactive ester or aldehyde derivative of PEG, under conditions where one or more PEG groups are attached. to the antibody or antibody fragment. Pegylation of the antibody can be carried out by an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer). As used herein, the term "polyethylene glycol" is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (C1-C10) alkoxy or aryloxy polyethylene glycol or polyethylene glycol maleimide. The antibody to be pegylated may be an aglycosylated antibody. Methods for pegylating proteins are known in the art and can be applied to the antibodies described herein (EP 0154316 and EP 0401384). In addition, antibodies can be chemically modified by conjugating or fusing the antigen-binding region of the antibody to serum protein, such as human serum albumin, to increase the half-life of the resulting molecule. Such an approach is described, for example, in the documents EP 0322094 and EP 0486525. The antibodies or fragments thereof of the present disclosure can be conjugated to a diagnostic agent and used diagnostically, for example, to monitor the development or progression of a disease and to determine the efficacy of a given treatment regimen. Examples of diagnostic agents include enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive materials, positron-emitting metals using various positron emission tomography scans, and non-radioactive paramagnetic metal ions. The detectable substance can be coupled or conjugated directly to the antibody or fragment thereof, or indirectly, via a linker using methods known in the art. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase or acetylcholinesterase. Examples of suitable prosthetic group complexes include streptavidin / biotin and avidin / biotin. Examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine, fluorescein, dansyl chloride, or phycoerythrin. An example of a luminescent material includes luminol. Examples of bioluminescent materials include luciferase, luciferin, and aequorin. Examples of suitable radioactive material include 125l, 1311, Indium-111, Lutetium-171, Bismuth-212, Bismuth-213, Astatine-211, Copper-62, Copper-64, Copper-67, Tritrium-90, Rcncrn / Lznza / YiAi Iodine-125, Iodine-131, Phosphorus-32, Phosphorus-33, Scandium-47, Silver-111, Gallium-67, Praseodymium-142, Samarium-153, Terbium-161, Dysprosium-166, Holmium-166, Rhenium-186, Rhenium-188, Rhenium-189, Lead-212, Radium-223, Actinium-225, Iron-59, Selenium-75, Arsenic-77, Strontium-89, Molybdenum-99, Rhodium-1105, Palladium-109, Praseodymium- 143, Promethium-149, Erbium-169, Iridium-194, Gold-198, Gold-199 and Lead-211. Monoclonal antibodies can be indirectly conjugated to radiometal ions through the use of bifunctional chelating agents that are covalently attached to the antibodies. Chelating agents can be attached via amites (Meares et al. (1984) Anal. Biochem. 142:68-78); sulfhifryl groups (Koyama (1994) Chem. Abstr. 120:217-262) of amino acid residues and carbohydrate groups (Rodwell et al. (1986) PNAS USA 83:2632-2636; Quadri et al. (1993) Nucí. Med. Biol. 20:559-570). In addition, the antibodies or fragments thereof of the present disclosure can be conjugated to a therapeutic agent. Suitable therapeutic agents include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetin, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin, antimetabolites (such as methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, fludarabine, 5-fluoroazine, ascyl gemcitabinc, cladribine), alkylating agents (such as mechlorethamine, thioepa, chloramhucil, melphalan , carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, dacarbazine (DTIC), procarbazine, mitomycin C, cisplatin and other platinum derivatives such as carboplatin), antibiotics (such as dactinomycin (formerly actinomycin), bleomycin , daunorubicin (formerly daunomycin), doxorubicin, idarubicin, mithramycin, mitomycin, mitoxantrone, plicamycin, anthramycin (AMC)), diphtheria toxin and related molecules (such as diphtheria A chain and active fragments thereof and hybrid molecules), toxin toxin (such as ricin A or a deglycosylated ricin chain toxin), cholera toxin, a Shiga-like toxin (SLT-I, SLT-II, SLT-IIV), LT toxin, C3 toxin, Shiga toxin, pertussis, tetanus toxin, soybean Bowman-Birk protease inhibitor, Pseudomonas exotoxin, allorin, saporin, modecin, gelanin, abrin A-chain, modecin A-chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolacca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogelin, restrietocin, fenomycin, enomycin toxins, and mixed toxins. Additional suitable conjugated molecules include ribonuclease (RNase), DNase I, an antisense nucleic acid, an inhibitory RNA molecule such as an siRNA molecule, an immunostimulatory nucleic acid, aptamers, ribozymes, triplex-forming molecules, and foreign leader sequences. Aptamers are small nucleic acids that vary Rcnccn / Lznza / YiAi 15 to 50 bases in length that fold into defined secondary and tertiary structures, such as stem loops or G quartets, and can bind small molecules, such as ATP (US Patent No. 5,631,146) and theophylline (US Patent 5,580,737), as well as large molecules such as reverse transcriptase (US Patent 5,786,462) and thrombin (US Patent 5,543,293). Ribozymes are nucleic acid molecules that are capable of catalyzing a chemical reaction, either intramolecularly or intermolecularly. Ribozymes typically cleave nucleic acid substrates by recognizing and binding to the target substrate with subsequent cleavage. Nucleic acid molecules with triplex-forming function can interact with either double- or single-stranded nucleic acid to form a triplex, in which three DNA strands form a complex that depends on Watson-Crick and Hoogsteen base pairing. Triplex molecules can bind to target regions with high affinity and specificity. Functional nucleic acid molecules may act as effectors, inhibitors, modulators, and stimulators of a specific activity possessed by a target molecule, or functional nucleic acid molecules may possess de novo activity independent of any other molecule. Therapeutic agents can be attached to the antibody directly or indirectly, using any of the numerous methods available. For example, an agent can be attached to the hinge region of the reduced antibody component by disulfide bond formation, using crosslinkers such as N-succinyl 3-(2-pyridylthio)propionate. (SPDP), or via a carbohydrate moiety in the Fe Region of the antibody (Yu et al. 1994 Int. J. Cancer 56: 244; Upeslacis et al., “Modification of Antibodies by Chemical Methods,” in Monoclonal antibodies: principles and applications, Birch et al (eds.), pp. 187-230 (WileyLiss, Inc. 1995), Price, “Production and Characterization of Synthetic Peptide-Derived Antibodies,” in Monoclonal antibodies: Production, engineering and clinical application, Ritteret al (eds.), pp. 60-84 (Cambridge University Press 1995). Techniques for conjugating therapeutic agents to antibodies are well known (Amon et al. “Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy,” in Monoclonal Antibodies And Cancer Therapy; Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al. “Antibodies For Drug Delivery,” in Controlled Drug Delivery (2nd Ed.); Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review,” in Monoclonal Antibodies '84: Biological And Clinical Applications, Finchera et al. (eds.), pp. 475-506 (1985); Result, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody in Cancer Therapy," in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al. “The Preparation And Cytotoxic Properties Of Antibody Rcncrn / Lznza / YiAi Toxin Conjugales,” (1982) Immunol. Rev. 62:119-58). The antibodies described herein or antigen-binding regions thereof can be linked to another functional molecule, such as another antibody or ligand for a receptor, to generate a bispecific or multispecific molecule that binds to at least two or more binding sites. different binding or target molecules. Linkage of the antibody to one or more other binding molecules, such as another antibody, antibody fragment, peptide, or binding mimetic, can be accomplished, for example, by chemical coupling, genetic fusion, or non-covalent association. Multispecific molecules may further include a third binding specificity, in addition to the first and second target epitopes. Bispecific and multispecific molecules can be prepared using methods known in the art. For example, each hi-specific molecule binding unit can be generated separately and then conjugated to each other. When the binding molecules are proteins or peptides, a variety of coupling or crosslinking agents can be used for covalent conjugation. Examples of crosslinking agents include protein A, carbodiimide, N-succinimidyl-S-acetyl-thioacetate (SATA), 5,5'-dithiobis(2-nitroberizoic acid) (DTNB), o-phenylendimaleimide (oPDM), N -succinimidyl-3-(2-pyridyldithio)propionate (SPDP) and sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohaxane-l-carboxylate (sulfo-SMCC) (Karpovsky et al. (1984) J. Exp. Med 160:1686, Liu et al.(1985) Proc.Nati.Acad.Sci.USA 82:8648). When the binding molecules are antibodies, they can be conjugated by sulfhydryl linkage of the C-terminal hinge regions of the two heavy chains. The antibodies or fragments thereof of the present disclosure may be linked to a moiety that is toxic to a cell to which the antibody binds to form exhausting antibodies. The antibodies described herein can also be bound to solid supports, which are particularly useful for immunoassays or purification of the target antigen. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene. Antibodies can also bind to many different carriers. Therefore, this disclosure also provides compositions containing the antibodies and another substance, active or inert. Examples of well known carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylase, natural and modified cellulose, polyacrylamide, agarose, and magnetite. The nature of the carrier can be soluble or insoluble for the purposes described in this document. Other suitable carriers for binding monoclonal antibodies will be known to those skilled in the art, or will be able to determine them using routine experimentation. In some of the aspects of the antibodies provided in this document, the Rcncrn / Lznza / YiAi antibody is a full length antibody. In some of the aspects of the antibodies provided herein, the antibody is a monoclonal antibody. In some of the aspects of the antibodies provided herein, the antibody is a chimeric or humanized antibody. In some of the aspects of the antibodies provided herein, the antibody is selected from the group consisting of Fab, F(ab)'2, Fab', scFv, and Fv. In some of the aspects of the antibodies provided herein, the antibody comprises an Fc domain. In some of the aspects of the antibodies provided herein, the antibody is a non-human animal, such as a rat, sheep, bovine , canine, feline or rabbit. In some of the aspects of the antibodies provided herein, the antibody is a human or humanized antibody or is not immunogenic in a human. In some of the aspects of the antibodies provided herein, the antibody comprises a human antibody framework region. In other aspects, one or more amino acid residues in a CDR of the antibodies provided herein are replaced with another amino acid. The substitution may be conservative in the sense of being a substitution within the same family of amino acids. The naturally occurring amino acids can be divided into the following four families and conservative substitutions will occur within those families. 1) Amino acids with basic side chains: lysine, arginine, histidine. 2) Amino acids with acidic side chains: aspartic acid, glutamic acid 3) Amino acids with uncharged polar side chains: asparagine, glutamine, serine, threonine, tyrosine. 4) Amino acids with nonpolar side chains: glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan, cysteine. In another aspect, one or more amino acid residues of one or more CDRs of an antibody are added or deleted. Such additions or deletions occur at the N or C terminus of the CDR or at a position within the CDR. By varying the amino acid sequence of the CDRs of an antibody by amino acid addition, deletion, or substitution, various effects can be obtained such as increased binding affinity for the target antigen. It should be appreciated that antibodies of the present disclosure comprising such varied CDR sequences still bind to a DNABII protein with similar specificity and sensitivity profiles as the disclosed antibodies. This can be tested by binding assays. Rcncrn / Lznza / YiAi In a further aspect, the antibodies are characterized as being both immunodominant and immunoprotective, as determined using appropriate assays and screens. Functional analysis and antibodies The antibodies described herein can be used to purify the polypeptides described herein and to identify equivalent biological polypeptides and / or polynucleotides. They can also be used to identify agents that modify the function of the polypeptides described herein. These antibodies include polyclonal antisera, monoclonal antibodies, and various reagents derived from these preparations that are familiar to those skilled in the art and are described above. Antibodies that neutralize the activities of the proteins encoded by identified genes can also be used in vivo and in vitro to demonstrate function by adding such neutralizing antibodies in in vivo and in vitro test systems. They are also useful as pharmaceutical agents for modulating the activity of the polypeptides described herein. Various antibody preparations can also be used in analytical methods such as ELISA assays or Western blots to demonstrate expression of proteins encoded by the identified genes by test cells in vitro or in vivo. Fragments of such proteins generated by protease degradation during metabolism can also be identified using appropriate polyclonal antisera with samples derived from experimental samples. The antibodies described herein can be used for vaccination or to boost vaccination, alone or in combination with peptide or protein-based vaccines or dendritic cell-based vaccines. compositions This disclosure further provides a composition comprising, or alternatively consisting essentially of, or further consisting of one, two or more, three or more of: an agent that interferes with the binding of a polyamine to DNA in biofilm, an agent that depletes biofilm cations, an agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment, an agent that interferes with the binding of eDNA to a DNA-binding protein, and / or an antibacterial agent. In one aspect, the composition does not comprise, consists essentially of, or even further consists of an HMB1 protein, fragment or equivalent thereof. In another aspect, it comprises, consists essentially of, or even further consists of, a DNase. In a further aspect, it does not comprise, consists essentially of, or even further consists of, a DNase. In one embodiment, the composition comprises, or alternatively consists essentially of, or Rcncrn / Lznza / YiAi further consists of an agent that interferes with the binding of a polyamine to DNA in the biofilm and an agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment. In a second embodiment, the composition comprises, or alternatively consists essentially of, or additionally consists of, an agent that depletes biofilm cations, an agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its environment and an agent that interferes with the binding of eDNA to a DNA binding protein. In a third embodiment, the composition comprises, or alternatively consists essentially of, or further consists of an agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its environment and an agent that interferes with eDNA binding. to a DNA-binding protein. In a fourth embodiment, the composition comprises, or alternatively consists essentially of, or further consists of an agent an agent that interferes with the binding of a polyamine to DNA in the biofilm and an agent that interferes with the binding of eDNA to a binding protein. to DNA. In a fifth embodiment, the composition comprises, or alternatively consists essentially of, or further consists of an agent an agent that interferes with the binding of a polyamine to DNA in the biofilm and an agent that interferes with the binding of eDNA to a protein of DNA binding and / or an antibacterial agent. In a sixth embodiment, the composition comprises, or alternatively consists essentially of, or further consists of an agent, an agent that interferes with the binding of a polyamine to DNA in the biofilm, an agent that depletes cations of the biofilm, and an agent that interferes. with the binding of the eDNA to a DNA-binding protein. In a seventh embodiment, the composition comprises, or alternatively consists essentially of, or further consists of an agent, an agent that interferes with the binding of a polyamine to DNA in the biofilm, an agent that depletes cations from the biofilm, and an agent that interferes. with the conversion of B-DNA to Z-DNA in the biofilm or its local environment. The compositions of this disclosure may additionally comprise, or alternatively consist essentially of, or even additionally consist of a pharmaceutically acceptable carrier. In one aspect, the agent that interferes with the binding of a polyamine to DNA in biofilm comprises one or more of: a polyamine analogue difluoromethylornithine, trans-4-methylcyclohexylamine, sardomozide, methylglyoxal-bis[guanylhydrazone] (MGBG), 1-am ¡noox¡-3-aminopropane, oxaliplatin, cisplatin and / or dicyclohexylamine, a derivative of any of them, or a salt thereof. In another aspect, the biofilm cation-depleting agent comprises one or more of: a cation exchange resin, an aminopolycarboxylic acid, a crown ether, an aza crown, or a cryptand, sulfonate, sulfopropyl, phosphocellulose, phosphocellulose P11 and / or heparin sulfate, or a derivative or analogue thereof. In yet another aspect, the agent that interferes with the conversion of B-DNA to Z-DNA in the Rcncrn / Lznza / YiAi biofilm or its local environment comprises one or more of: HMGB1 protein, fragment or equivalent thereof, an anti-DNA-B antibody or fragment or derivative thereof, and / or chloroquine, or a derivative of any of them. In a particular aspect, the agent that interferes with the binding of eDNA to a DNA binding protein comprises one or more of an anti-DNABII antibody, an anti-IHF antibody and / or an anti-HU antibody, or fragments of each. one of them. Compositions are further provided. The compositions comprise a carrier and one or more of an isolated polypeptide described herein, an isolated polynucleotide described herein, a vector described herein, an isolated host cell described herein, a small molecule, or an antibody described herein. this document. The carriers can be one or more of a solid support or a pharmaceutically acceptable carrier. The compositions may further comprise an adjuvant or other components suitable for administrations as vaccines. In one aspect, the compositions are formulated with one or more pharmaceutically acceptable excipients, diluents, carriers, and / or adjuvants. Furthermore, embodiments of the compositions of the present disclosure include one or more of an isolated polypeptide disclosed herein, an isolated polynucleotide disclosed herein, a vector disclosed herein, a small molecule, an isolated host cell disclosed herein document or an antibody of the disclosure, formulated with one or more pharmaceutically acceptable substances. For oral preparations, one or more of an isolated or recombinant polypeptide as described herein, an isolated or recombinant polynucleotide as described herein, a vector as described herein, an isolated host cell as described herein document, a small molecule or an antibody as described herein may be used alone or in pharmaceutical formulations described herein comprising, or consisting essentially of, the compound in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch, or gelatins; with disintegrants, such as corn starch, potato starch, or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, wetting agents, preservatives, and flavoring agents. Pharmaceutically compatible binding agents and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or stearates; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. Pharmaceutical formulations and unit dosage forms suitable for oral administration are particularly useful in the treatment of chronic conditions, infections, and therapies in which the drug is self-administered by the patient. In one aspect, the formulation is specific for pediatric administration. The disclosure provides pharmaceutical formulations in which one or more of an isolated polypeptide disclosed herein, an isolated polynucleotide disclosed herein, a vector disclosed herein, an isolated host cell disclosed herein, or an antibody disclosed herein. document can be formulated into preparations for injection according to the disclosure by dissolving, suspending or emulsifying them in an aqueous or non-aqueous solvent, such as vegetable oils or the like, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, and preservatives or other antimicrobial agents. A non-limiting example of this is an antimicrobial agent, such as other components of the vaccine, such as surface antigens, for example, an OMP P5, OMP 26, OMP P2 or Pilin type IV protein (see Jurcisek and Bakaletz ( 2007) J. of Bacteriology 189(10): 3868-3875 and Murphy, TF, Bakaletz, LO & Smeesters, PR (2009) The Pediatric Infectious Disease Journal, 28: S121-S126) and antibacterial agents. For intravenous administration, suitable carriers include saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.), or phosphate buffered saline (PBS). In all cases, a composition for parenteral administration must be sterile and must be fluid to the extent that easy syringability exists. The aerosol formulations provided by the disclosure may be administered by inhalation and may be propellant or non-propellant. For example, the embodiments of the pharmaceutical formulations described herein comprise a compound described herein formulated in pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen, and the like. For administration by inhalation, the compounds may be administered in the form of an aerosol from a pressurized container or dispenser containing a suitable propellant, for example a gas such as carbon dioxide, or a nebulizer. A non-limiting example of a non-propellant is a spray pump that is ejected from a closed container by means of mechanical force (i.e., pushing down on a piston with your finger or by compression of the container, such as by an applied compression force). to the wall of the container or an elastic force exerted by Rcncrn / Lznza / YiAi the wall itself, for example, by an elastic bladder). The suppositories described herein can be prepared by mixing a compound described herein with any of a variety of bases such as emulsifying bases or water soluble bases. Embodiments of this pharmaceutical formulation of a compound described herein can be administered rectally via a suppository. The suppository may include vehicles such as cocoa butter, carbowaxes, and polyethylene glycols, which melt at body temperature but solidify at room temperature. Unit dosage forms for oral or rectal administration may be provided, such as syrups, elixirs, and suspensions, in which each dosage unit, eg, teaspoon, tablespoon, tablet, or suppository, contains a predetermined amount of the one-containing composition. or more compounds described in this document. Similarly, unit dosage forms for injection or intravenous administration may comprise a compound described herein in a composition such as a solution in sterile water, normal saline, or other pharmaceutically acceptable carrier. The embodiments of the pharmaceutical formulations described herein include those in which one or more of an isolated polypeptide described herein, an isolated polynucleotide described herein, a vector described herein, a small molecule for use in the disclosure, an isolated host cell described herein, or an antibody described herein is formulated into an injectable composition. The injectable pharmaceutical formulations described herein are prepared as liquid solutions or suspensions; or as solid forms suitable for solution or suspension in liquid vehicles prior to injection. The preparation can also be emulsified or the active ingredient encapsulated in liposomal vehicles according to other embodiments of the pharmaceutical formulations described herein. In one embodiment, one or more of an isolated polypeptide described herein, an isolated polynucleotide described herein, a vector described herein, an isolated host cell described herein, or an antibody described herein is formulated for use. administration through a continuous administration system. The term continuous delivery system is used interchangeably herein with controlled delivery system and encompasses continuous (eg, controlled) delivery devices (eg, pumps) in combination with catheters, injection devices and the like, a wide variety of known in the art. Mechanical or electromechanical infusion pumps may also be suitable for use with the present disclosure. Examples of such devices include those described in, for example, US Patent Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; Rcncrn / Lznza / YiAi Rcncrn / Lznza / YiAi 4,725,852; 5,820,589; 5,643,207; 6,198,966; and the like. In general, administration of a compound described herein can be accomplished using any of a variety of refillable pump systems. The pumps provide a constant and controlled release over time. In some embodiments, a compound described herein is in a liquid formulation in a drug-impermeable reservoir and is continuously administered to the individual. In one embodiment, the drug delivery system is an at least partially implantable device. The implantable device can be implanted at any suitable implantation site using methods and devices well known in the art. An implantation site is a site within the body of a subject into which a drug delivery device is inserted and placed. Implantation sites include, but are not necessarily limited to, a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body. Subcutaneous implantation sites are used in some modalities due to the convenience of implantation and removal of the drug delivery device. Drug delivery devices suitable for use in the disclosure may be based on any of a variety of modes of operation. For example, the drug delivery device can be based on a diffusive system, a convective system, or an erodible system (eg, an erosion-based system). For example, the drug delivery device can be an electrochemical pump, an osmotic pump, an electroosmotic pump, a vapor pressure pump, or an osmotic disruption matrix, for example, when the drug is incorporated into a polymer and the polymer provides for release of the drug formulation concomitant with degradation of a drug-impregnated polymeric material (eg, a biodegradable drug-impregnated polymeric material). In other embodiments, the drug delivery device is based on an electrodiffusion system, an electrolytic pump, an effervescent pump, a piezoelectric pump, a hydrolytic system, etc. Drug delivery devices based on a mechanical or electromechanical infusion pump may also be suitable for use with the present disclosure. Examples of such devices include those described in, for example, US Patent Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852; and the like. In general, a method of treating a subject can be accomplished using any of a variety of non-interchangeable, rechargeable pump systems. Pumps and other convection systems can be used due to their generally more consistent controlled release over time. Osmotic pumps are used in some modalities due to their combined advantages of more consistent controlled release and relatively small size (see, for example, Rcncrn / Lznza / YiAi example, PCT International Application Publication No. WO 97 / 27840 and US Patent Nos. 5,985,305 and 5,728,396). Exemplary osmotically driven devices suitable for use in the disclosure include, but are not necessarily limited to, those described in US Patent Nos. 3,760,984; 3,845,770; 3,916,899; 3,923,426; 3,987,790; 3,995,631; 3,916,899; 4,016,880; 4,036,228; 4,111,202; 4,111,203; 4,203,440; 4,203,442; 4,210,139; 4,327,725; 4,627,850; 4,865,845; 5,057,318; 5,059,423; 5,112,614; 5,137,727; 5,234,692; 5,234,693; 5,728,396; and the like. Another exemplary device that can be adapted for the present disclosure is the Synchromed infusion pump (Medtronic). In some embodiments, the drug delivery system is an implantable device. The drug delivery device can be implanted at any suitable implantation site using methods and devices well known in the art. As noted herein, an implantation site is a site within a subject's body into which a drug delivery device is inserted and placed. Implantation sites include, but are not necessarily limited to, a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body. Suitable excipient vehicles for a compound described herein are, for example, water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof. In addition, if desired, the carrier may contain minor amounts of auxiliary substances such as wetting or emulsifying agents or pH buffering agents. Methods for preparing dosage forms for these are known, or will become apparent upon consideration of this description, to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17th Edition, 1985. The composition or formulation to be administered will, in any event, contain an amount of the compound adequate to achieve the desired condition in the subject being treated. being treated. The compositions of the present disclosure include those that comprise a sustained release or controlled release matrix. Furthermore, the embodiments of the present disclosure can be used in conjunction with other treatments using sustained release formulations. As used herein, a sustained release matrix is ​​a matrix made of materials, generally polymers, that are degradable by acid-based or enzymatic hydrolysis or by solution. Once inserted into the body, enzymes and body fluids act on the matrix. A sustained release matrix is ​​desirably chosen from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid), polyanhydrides, poly(ortho)esters , polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylatanine, tyrosine, isoleucine, polynucleotides, polyvinylpropylene, polyvinylpyrrolidone, and silicone. Illustrative biodegradable matrices include a polylactide matrix, a polyglycolide matrix, and a polylactide co-glycolide matrix (copolymers of lactic acid and glycolic acid). In another embodiment, the agent (as well as the combination compositions) is administered in a controlled release system. For example, a compound described herein can be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used (Sefton (1987) CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al. (1980) Surgery 88:507; Saudek et al. (1989) N. EngL J 321:574). In another embodiment, polymeric materials are used. In yet another embodiment, a controlled release system is placed in close proximity to the therapeutic target, ie, the liver, thereby requiring only a fraction of the systemic dose. In yet another embodiment, a controlled release system is placed in close proximity to the therapeutic target, whereby only a fraction of the systemic is required. Other controlled release systems are discussed in the review by Langer (1990) Science 249:1527-1533. In another embodiment, the compositions of the present disclosure (as well as combination compositions separately or together) include those formed by impregnating an inhibitory agent described herein into absorbent materials, such as sutures, bandages, and gauze pads, or coated onto the surface of solid phase materials, such as surgical clips, zippers, and catheters to deliver the compositions. Other such delivery systems will be readily apparent to those skilled in the art in view of the present disclosure. The present disclosure provides methods and compositions for the administration of one or more agents to a host (eg, a human) for the treatment of a microbial infection. In various embodiments, these methods described herein encompass almost any available method and route suitable for drug delivery, including in vivo and ex vivo methods, as well as localized and systemic routes of administration. screening assays The present disclosure provides methods for screening for equivalent agents, such as monoclonal antibodies equivalent to a polyclonal antibody as described herein and various agents that modulate the activity of the active agents and pharmaceutical compositions disclosed herein or the function of a polypeptide or peptide product encoded by the polynucleotide described herein. For the purposes of this disclosure, an agent includes, but is not limited to, a biological or chemical compound, such as a simple or complex organic or inorganic molecule, a peptide, a protein Rcncrn / Lznza / YiAi Rcncrn / Lznza / YiAi (eg, an antibody, an antisense polynucleotide) or a ribozyme. A wide range of compounds can be synthesized, for example polymers, such as polypeptides and polynucleotides, and synthetic organic compounds based on various backbone structures, and these are also included in the term agent. In addition, various natural sources can provide compounds for screening, such as plant or animal extracts, and the like. It is to be understood, although not always explicitly stated, that the agent is used alone or in combination with another agent, which has the same or different biological activity as the agents identified by the inventive screen. As is apparent to one skilled in the art, suitable cells can be grown in microtiter plates and various agents can be assayed at the same time by observing genotypic changes, phenotypic changes, or a reduction in microbial titer. When the agent is a composition other than DNA or RNA, such as a small molecule as described above, the agent can be added directly to cell culture or added to culture medium for addition. As is apparent to those skilled in the art, an effective mount must be added that can be determined empirically, When the agent is an antibody or an antigen-binding fragment, the agent can be contacted or incubated with the target antigen and polyclonal antibody as described herein under conditions to perform a competitive ELISA. Such methods are known to the person skilled in the art. The assays can also be performed on a subject. When the subject is an animal such as a rat, chinchilla, mouse, or ape, the method provides a convenient animal model system that can be used prior to clinical testing of an agent in a human patient. In this system, a candidate agent is a potential drug if the symptoms of the disease or microbial infection are reduced or eliminated, each compared to the untreated animal having the same infection. It may also be useful to have a separate negative control group of healthy, untreated cells or animals, providing a basis for comparison. The agents and compositions can be used in the manufacture of medicaments and for the treatment of humans and other animals by administration in accordance with conventional procedures, such as an active ingredient in pharmaceutical compositions. combination therapy The compositions and related methods of the present disclosure may be used in combination with the administration of other therapies. These include, but are not limited to, the administration of DNase enzymes, antibiotics, antimicrobials, or other antibodies. In one aspect, the agent is administered in the absence of a DNase enzyme. Rcncrn / Lznza / YiAi 100 In other embodiments, the methods and compositions may be combined with antibiotics and / or antimicrobials. Antimicrobials are substances that kill or inhibit the growth of microorganisms such as bacteria, fungi, or protozoa. Although biofilms are generally resistant to the actions of antibiotics, the compositions and methods described herein can be used to sensitize infection involving a biofilm to traditional therapeutic methods for treating infections. In other embodiments, the use of antibiotics or antimicrobials in combination with methods and compositions described herein allows for reduction of the effective amount of the antimicrobial and / or biofilm-reducing agent. Some non-limiting examples of antimicrobials and antibiotics useful in combination with the methods of the current disclosure include amoxicillin, amoxicillin-clavulanate, cefdinir, azithromycin, and sulfamethoxazole trimethoprim. The therapeutically effective dose of the antimicrobial and / or antibiotic in combination with the biofilm reducing agent can be readily determined by conventional methods. In some modalities, the dose of the antimicrobial agent in combination with the biofilm-reducing agent is the median effective dose that has been shown to be effective in other bacterial infections, for example, bacterial infections where the etiology of the infection does not include a biofilm. . In other modalities, the dose is 0.1, 0.15, 0.2, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.8, 0.85, 0.9, 0.95, 1.1, 1.2, 1.3. , 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0 or 5 times the mean effective dose. The antibiotic or antimicrobial can be added before, at the same time, or after the addition of the anti-DNABII antibody. In other embodiments, the methods and compositions can be combined with antibodies that treat the bacterial infection. An example of an antibody useful in combination with the methods and compositions described herein is an antibody directed against an unrelated outer membrane protein (ie, OMP P5). Treatment with this antibody alone does not reduce the volume of a biofilm in vitro. Combined therapy with this antibody and a biofilm reducing agent results in a greater effect than could be achieved with either reagent used alone at the same concentration. Other antibodies that may produce a synergistic effect when combined with a biofilm reducing agent or methods for reducing a biofilm include anti-OMP26 anti-rsPilA, anti-OMP P2, and complete anti-OMP preparations. The compositions and methods described herein can be used to sensitize bacterial infection involving a biofilm to common therapeutic modalities effective in treating bacterial infections without a biofilm, but are otherwise ineffective in treating bacterial infections involving a biofilm. biofilm. In other modalities, the compositions and methods described herein can be used in combination with therapeutic modalities that are effective in treating Rcncrn / Lznza / YiAi 101 bacterial infections involving a biofilm, but the combination of said additional therapy and biofilm-reducing agent or method produces a synergistic effect such that the effective dose of the biofilm can be reduced by the additional biofilm-reducing agent or therapeutic agent. In other cases, the combination of such additional therapy and biofilm-reducing agent or method produces a synergistic effect so that treatment is improved. An improvement in treatment may be evidenced by a shorter amount of time required to treat the infection. The additional therapeutic treatment can be added before, at the same time or after the methods or compositions used to reduce the biofilm, and can be contained within the formation itself or as a separate formulation. kits Provided herein are kits comprising, or alternatively consisting essentially of, or further consisting of the composition described herein and instructions for use. In one aspect, the instructions for use provide instructions for performing any of the methods described in this document. In one aspect, one or more, two or more, or three or more of the agents for use in the described methods are packaged independently or together in the kit. Kits containing the agents and instructions necessary to perform the in vitro and in vivo methods as described herein are also claimed. Accordingly, the disclosure provides kits for performing these methods that may include what is described herein, as well as instructions for carrying out the methods described herein, such as collecting tissue and / or performing detection, and / or testing. the results, and / or administration of an effective amount of an agent as defined herein. These can be used alone or in combination with other suitable antimicrobial agents. The following examples are intended to illustrate, and not limit, the modalities described in this document. Experiment No. 1 Polyamines are ubiquitous small aliphatic polycations produced and used by almost all living organisms. Michael et al. (2016) J Biol Chem. 291(29): 14896-903; D'Agostino et al. (2005) FEBS J. 272(15):3777-87. Derivatives of amino acids, they play roles in a multitude of cellular functions critical to growth and proliferation, including transcription, translation, regulation of transcription, autophagy, and resistance to stress. Miller-Fleming et al (2015) J Mol Biol 427(21):3389-406. There are multiple routes for the synthesis of polyamines and their presence in the metabolic repertoire varies between species. Michael et al. (2016) Biochem J. 473(15):2315-29. Due to the nonspecific nature Rcncrn / Lznza / YiAi In addition to its electrostatically mediated interactions, polyamine synthesis is tightly regulated through a combination of transcription, translation, and protein degradation mechanisms. Miller-Fleming et al. (2015) J Mol Biol 427(21):3389-406. There are five primary polyamine molecules produced by living organisms; spermine, spermidine, putrescine, cadaverine, and 1,3-diaminopropane. Miller-Fleming et al. (2015) J Mol Biol 427(21):3389-406. Additional types of polyamines are produced in a more species-specific manner. Each polyamine has slightly different attributes, due to differences in the length and number of amine groups that dictate cationic character and charge distribution. Michael et al. (2016) J Biol Chem. 291(29):14896-903. This variation allows some level of specificity in polyamine activity, as well as directs the assembly of polyamine aggregates. D'Agostino et al. (2005) FEBS J. 272(15):3777-87; D'Agostino et al. (2006) IUBMB Life 58(2):75-82. The function of polyamines is concentration dependent, as evidenced by the multiple disease states that correlate with dysregulation of polyamine concentrations. Miller-Fleming et al. (2015) J Mol Biol 427(21):3389-406. General metabolic processes can be altered due to altered polyamine levels, and specific processes can be altered by specific or general changes in polyamine levels. For example, specific concentrations of polyamines can mediate different outcomes for the production of microbial biofilms. In multiple species, intracellular polyamine levels have been shown to regulate biofilm biogenesis and that this regulation is likely due to intracellular sensing of specific polyamines. Karatan et al. (2013) Biotechnol Lett. 35(11):1715-7; McGinnis et al. (2009) FEMS Microbiol Lett. 299(2):166-74; Wortham et al. (2010) Environ Microbiol. 12(7):2034-47. The polyamines that mediate these phenotypes may be species-specific. In mutant strains lacking the ability to produce a specific polyamine, exogenous addition of that polyamine that cannot be synthesized restored biofilm formation, whereas addition of other polyamines did not. In addition, the literature is replete with examples of bacterial biofilm formation being inhibited by endogenous or high concentrations of specific exogenous polyamines and their derivatives, while other polyamines have no effect. Karatan et al. (2013) Biotechnol Lett. 35(11):1715-7; Goytia et al. (2013) FEMS Microbiol Lett. 343(1):64-9; Cardile et al. (2017) Adv Exp Med Biol. 973:53-70; Wang et al. (2016) J Bacteriol. 198(19):2682-91; How are you. (2016) Microbiology open. 5(3):402-12; Konai et al. (2015) Bioconjug Chem. 26(12):2442-53; Yes et al. (2015) Appl Microbiol Biotechnol. 99(24):10861-70; Dewangan et al. (2014) Antimicrob Agents Chemother. 58(9):5435-47; Ding et al. (2014) Appl Environ Microbiol. 80(4):1498-506; Planet et al. (2013) MBio. 4(6):e00889-13. However, the same polyamines that inhibit a species may not inhibit biofilm biogenesis and may even Rcncrn / Lznza / YiAi 103 may be required for biofilm production in other bacterial species. Karatan et al. (2013) Biotechnol Lett. 35(11):1715-7; McGinnis et al. (2009) FEMS Microbiol Lett. 299(2)1166-74; Wortham et al. (2010) Environ Microbiol. 12(7):2034-47; Wang et al. (2016) J Bacteriol. 198(19)12682-91; Hobley et al. (2017) J Biol Chem. 292(29)112041-53; Ouetal. (2017) Mol Med Rep. 15(1)121-20; Nesse et al. (2015) Appl Environ Microbiol. 81(6)12226-32; Ramon Perez et al. (2015) Microb Pathog. 79:8-16; Hobley et al. (2014) Cell. 156(4):844-54; Sakamoto et al. (2012) Int J Biochem Cell Biol. 44(11)11877-86; Burrell et al. (2010) J Biol Chem. 285(50)139224-38; Lee et al. (2009) J Biol Chem. 284(15)19899-907; Patel et al. (2006) J Bacteriol. 188(7):2355-63. Furthermore, although the role of polyamines in fungal biofilm development is less well defined, Candida albicans polyamine synthesis mutants are defective for biofilm production and treatment of C. albicans with polyamine synthesis inhibitors affects negatively the growth of biofilms. Chen et al. (2014) Mol Biosyst. 10(1):74-85; Liao et al. (2015) Int J Antimicrob Agents. 46(1):4552. A potential source of eDNA stabilization is the presence of polyamines in the biofilm matrix. Polyamines have been shown to modulate DNA structure (Pasini et al. (2014) Amino Acids. 46(3):595-603) and protect DNA from external modifying agents or hazardous conditions. Dagostino et al. (2005) FEBS J. 272(15):3777-87; Baeza et al. (1991) Orig Life Evol Biosph. 21(4):225-42; Nayvelt et al. (2010) Biomacromolecules. 11(1):97-105. The role of polyamines in stabilizing intracellular chromatin is well documented. Pasini et al. (2014) Amino Acids. 46(3):595-603. Here, applicants hypothesized that extracellular polyamines stabilize the eDNA structure of bacterial biofilms and demonstrate that they alter polyamine content and the ability of polyamines to bind eDNA in the biofilm matrix extracellularly as a means to disrupt bacterial biofilm communities. Applicants found that inhibition of polyamine synthesis or antagonism disrupted established bacterial biofilms and that supplementation of polyamine-depleted bacteria restored eDNA structure. Polyamines are present in the extracellular matrix of bacterial biofilms. To determine whether polyamines were present in the biofilm matrix, as a model human pathogen, applicants cultured nontypeable Haemopilus influenzae (NTHi) biofilms in vitro and performed immunofluorescence with antibodies directed against putrescine, spermine, or spermidine. The localization of polyamines within the biofilm extracellular matrix was visualized using confocal laser scanning microscopy (CLSM; Figure 12). All three polyamines were detected by immunofluorescence microscopy throughout the biofilm. Rcncrn / Lznza / YiAi 104 Inhibition of polyamine synthesis or polyamine antagonism disrupts bacterial biofilms Dicyclohexylamine inhibits spermidine synthase by a competitive inhibition mechanism, ie, by binding to the same site on the protein as the putrescine substrate. Therefore, Applicants hypothesized that dicyclohexylamine would inhibit the development of NTHi biofilms. First, applicants confirmed that dicyclohexylamine did not affect NTHi growth up to 10 mM (Figure 13). However, the addition of 50μΜ dicyclohexylamine significantly inhibited NTHi biofilm formation as assessed by COMSTAT analysis, reducing biofilm thickness and biomass by approximately 40% while increasing biofilm roughness (Figure 14). . Subsequent immunofluorescence microscopy to detect the presence of spermidine in dicyclohexylamine-treated residual NTHi biofilms revealed a corresponding statistically significant decrease in spermidine present in the biofilm matrix (Figure 15). Dicyclohexylamine also reduced the number and complexity of eDNA scaffold structures produced during early biofilm formation (Figure 16). The exogenous addition of 1 mM spermidine to dicyclohexylamine-treated NTHi biofilms restored the biofilm to normal thickness, biomass, and roughness (Figure 14), indicating that dicyclohexylamine functioned as a competitive inhibitor of spermidine synthase or exogenous spermidine in the extracellular matrix of the biofilm. These data reveal that, through inhibition of polyamine synthesis or antagonistic binding to polyamine binding sites, compounds targeting extracellular polyamines that bind to eDNA in the biofilm matrix have the potential to prevent the biogenesis of polyamines. biofilm and the breakdown of established biofilms. Experiment No. 2 The pathogenesis of >80% of all bacterial infectious diseases is estimated to include a biofilm state necessary in the pathogenesis of the disease course, according to the Centers for Disease Control and Prevention. Biofilms are composed of bacterial cells attached to abiotic and biotic surfaces that have progressed into a structured population that is embedded within an extracellular polymeric substance (EPS) that includes nucleic acids, proteins, lipids, and biopolymers (Davies (2003) Nat Rev Drug Discov. 2(2):114-22), and bivalent cations (Cavaliere et al., (2014) Microbiology Open. 3(4):557-567). EPS acts as a protective barrier against harsh environments and antimicrobial agents such as antibiotics and host immune effectors (Devaraj et al., (2013), supra. Crucial structural and architectural components of the biofilm matrix are extracellular DNA (eDNA ) and the Rcncrn / Lznza / YiAi 105 DNABII family of DNA binding proteins (IHF and HU). DNABII proteins bind with high affinity to eDNA, allowing biofilm stabilization. Antibodies that target DNABII induce biofilm collapse with the release of resident bacteria in vitro and in vivo (Novotny et al. (2016)_EBioMedicine. (10):33-44); and Goodman et al. (2011) Mucosal Immunology. 4(6):625-637. Although DNase treatment can prevent bacterial species from forming a biofilm, it has little or no effect on pre-existing biofilms (Flemming and Wingender, (2010) Nature Reviews Microbiology. 8:623-633. Positively charged divalent cations (Mg2+ , Mn2+, Zn2+, Cu2+ and Ca2+) mediate intermolecular crosslinking between adjacent negatively charged DNA molecules.This interaction stabilizes the DNA structure and subsequent DNA-protein interactions (Gueroult et al. (2012) PLOS ONE. (7)- 7-e41704, and Tan and Chen, (2006) Biophysical Journal.(90):1175-1190, Hackl et al.(2005) International Journal of Biological Macromolecules 35:175-191.In addition, the removal of Mg2+ cations of biofilms increases the susceptibility of nontypable Haemophilus influenzae (NTHi) to antibiotic treatment (Cavaliere et al. (2014) Microbiology Open. 3(4):557-567. Finally, polyamines (short polycationic biogenic amines) are also important for biofilm formation by multiple bacterial species (Patel et al. (2006) Journal of Bacteriology. 2355-2363; and Hobley et al., (2017) Journal of Biological Chemistry. 292(29): 12041-12053. CLSM immunofluorescence (IF) images of biofilms formed by many pathogenic bacteria when probed for the presence of spermidine indicate that polyamines are part of the EPS of bacterial biofilms and, furthermore, that they co-localize with the HU protein. DNABII (Figure 17A). Inhibition of the spermidine biosynthesis pathway in NTHI by the enzyme inhibitor dicyclohexylamine (DCHA) results in an overall decrease in spermidine levels as measured by IF and a significant decrease in average biofilm thickness, indicating that polyamines are critical for the stability of biofilms (Figure 17B and Figure 17C). The ability of microorganisms to form biofilms is highly problematic and is present in a wide range of industries. For example, nosocomial infections associated with mechanical heart valve devices, urinary catheters, and venous catheters are the result of bacterial contamination in the form of a biofilm (Donlan, (2001) Emerging Infectious Diseases. 7(2):277-281. Control of biofilm formation in agriculture and food processing facilities is also important for the prevention of disease and major food loss Chmielewski and Frank (2006) Compr Rev Food Sci F 2:22-32. Wastewater treatment facilities also develop biofilm-mediated problems such as biofouling, EPS buildup, and microorganisms that prevent adequate membrane filtration, leading to Rcncrn / Lznza / YiAi 106 water pollution (Wood et al., (2016) PNAS. E2802-E2811). Surface coating and / or treatment of biofilms with cation exchange resins (sulfonate, sulfopropyl, phosphocellulose, or heparin sepharose) utilizes the properties of negatively charged resin chemistry to target the positively charged components of the EPS (i.e. , polyamines, divalent metal cations and DNABII proteins). This results in the breakage and prevention of biofilm on biotic and abiotic surfaces. Here applicants demonstrate that P11 phosphocellulose and heparin sepharose cation exchange resins prevent biofilm formation and are capable of disrupting preformed biofilms. Cation exchange resins have a negative effect on preformed biofilms and biofilm formation by nontypable Haemophilus influenzae (NTHI). Applicants questioned whether negatively charged resins unable to penetrate biofilms could act to titrate positively charged molecules (ie, polyamines, divalent metal cations, and DNABII proteins) that are universally required for bacterial biofilm formation. Two resins were chosen, for example, phosphocellulose (P11) and heparin sepharose, which are cation exchangers used for ion exchange chromatography, but are also used for affinity purification of DNABII proteins (Nash et al. (1987) Journal of Bacteriology 4124-4127 and Vorgias and Wilson, (1991) Escherichia coli Protein Expression and Purification 2(5-6):317-20). To determine the anti-biofilm activity of cation exchange resins in preformed biofilms (ie, the ability to break an existing biofilm), NTHI growth was initiated and maintained for 24 hours, then treated for 16 hours with 0 (sBHI control), 0.1, 1 or 5% (w / v) P11 phosphocellulose (Figure 18A). To determine the anti-biofilm activity of cation exchange resins to prevent biofilm formation, NTHI growth was initiated and maintained in the presence of 0 (control sBHI), 0.1, 1, and 5% w / v phosphocellulose P11. (Figure 18B) or 5% (w / v) heparin sepharose (Figure 19). Biofilms were washed with saline and stained with LIVE / DEAD®, visualized with confocal scanning microscopy (CSLM) and analyzed by COMSTAT to determine average thickness and biomass. As indicated in Figure 18, P11 phosphocellulose had a negative effect on both preformed biofilms (it was able to break) and biofilm formation (it was able to prevent) which was revealed by the decrease in average thickness and the biomass. Heparin Sepharose also had a negative effect on biofilm formation where a decrease in average thickness and biomass was observed (Figure 18). These data suggest that cation exchange resins can alter and prevent biofilm formation in vitro. DNABII (HU) partially restored depleted preformed NTHí biofilms in 107 cations. To determine if removal of DNABII proteins was partly responsible for the observed biofilm disruption and prevention, NTHI growth was initiated and maintained in the presence of 0 (sBHI control) or 1% (w / v) phosphocellulose P11. ) for 24 hours with the exogenous addition of HU protein at 1 or 5 ug / ml for 16 hours. Biofilms were washed with saline and stained with LIVE / DEAD®, visualized with CSLM, and analyzed by COMSTAT for average thickness and biomass. As shown in Figure 19, HU can partially offset the negative effect of phosphocellulose in vitro. These data suggest that HU is the target of the cation exchange resin. Divalent metals partially restore cation depleted preformed NTHI biofilms. To determine if Mg2+ can restore cation-depleted biofilms, NTHI growth was initiated and maintained in the presence of 0 (sBHI control) or 1% (w / v) phosphocellulose P11 for 24 hours with exogenous addition of MgCI2( 0-10 mM) for 16 hours. Biofilms were washed with saline and stained with LIVE / DEAD®, visualized with CSLM, and analyzed by COMSTAT for average thickness and biomass. As shown in Figure 20, MgCI2 can partially compensate for the disruptive effect of phosphocellulose in vitro. These data suggest that P11 phosphocellulose depletes divalent metals from the biofilm matrix. Spermidine partially restores preformed and cation depleted NTHI biofilms To determine if spermidine can restore cation-depleted biofilms, NTHI growth was initiated and maintained in the presence of 0 (sBHI control) or 1% (w / v) phosphocellulose P11 for 24 hours with exogenous addition of spermidine ( 0-5 mM) for 16 hours. Biofilms were washed with saline and stained with LIVE / DEAD®, visualized with CSLM, and analyzed by COMSTAT for mean thickness and biomass. As shown in Figure 21, spermidine can partially offset the negative effect of phosphocellulose in vitro. These data suggest that P11 phosphocellulose depletes biofilm matrix polyamines. The cation depleting effects of P11 phosphocellulose do not require direct contact with the biofilm. To determine if the decrease in biofilm formation was d...

Claims

1. A method for inhibiting the stability of a biofilm, characterized in that it comprises contacting the biofilm with an effective amount of an agent that interferes with the binding of a polyamine to DNA in the biofilm, wherein the agent is not an HMGB1 protein, a fragment or an equivalent of each.

2. A method for treating a biofilm in a subject, characterized in that it comprises administering to the subject infected with a biofilm an effective amount of an agent that interferes with the binding of a polyamine DNA in the biofilm, wherein the agent is not an HMGB1 protein, a fragment or an equivalent thereof.

3. A method for preventing the formation of a biofilm in a subject susceptible to developing a biofilm, characterized in that it comprises administering to the subject an effective amount of an agent that interferes with the binding of a polyamine to DNA in the biofilm, optionally wherein the agent is not an HMGB1 protein, a fragment or an equivalent thereof.

4. A method for treating an infection caused by a biofilm-producing bacterium in a subject in need thereof, the method being characterized in that it comprises administering to the subject an effective amount of an agent that interferes with the binding of a polyamine to DNA in the biofilm and an agent that inhibits the replication of the organism, optionally wherein the agent is not an HMGB1 protein, a fragment or an equivalent thereof.

5. A method for inhibiting the stability of a biofilm, characterized in that it comprises contacting the biofilm with an effective amount of one or more agents that interfere with the binding of a polyamine to DNA in the biofilm, wherein the agent is not an HMGB1 protein, a fragment or an equivalent thereof.

6. A method for treating a biofilm in a subject, characterized in that it comprises administering to the subject infected with a biofilm an effective amount of one or more agents that interfere with the binding of a polyamine DNA in the biofilm, wherein the agent is not an HMGB1 protein, a fragment or an equivalent thereof.

7. A method for preventing the formation of a biofilm in a subject susceptible to developing a biofilm, characterized in that it comprises administering to the subject an effective amount of one or more agents that interfere with the binding of a polyamine Rcncrn / Lznza / YiAi 156 to DNA in the biofilm, optionally wherein the agent is not an HMGB1 protein, a fragment or an equivalent thereof.

8. A method for treating an infection caused by a biofilm-producing bacterium in a subject in need thereof, the method being characterized in that it comprises administering to the subject an effective amount of one or more agents that interfere with the binding of a polyamine to DNA in the biofilm and an agent that inhibits the replication of the organism, optionally wherein the agent is not an HMGB1 protein, a fragment or equivalent thereof.

9. The method according to claim 1 or 5, characterized in that the contact is in vitro or in vivo.

10. The method according to any of claims 1, 5 or 9, characterized in that the agent interfering with the binding of a polyamine to DNA in the biofilm is a tRNA.

11. The method according to any of the preceding claims, characterized in that the agent is an inhibitor of polyamine synthesis or an agent that inhibits the binding of polyamine to DNA, wherein the agent is not an HMGB1 protein, a fragment or an equivalent thereof.

12. The method according to any of the preceding claims, characterized in that the polyamine is selected from the group of: putrescine, spermine, cadaverine, 1,3-diaminopropane or spermidine.

13. The method according to claim 11, characterized in that the agent comprises a polyamine analogue of difluoromethylornithine, trans-4-methylcyclohexylamine, sardomozide, methylglyoxal-bis[guanylhydrazone] (MGBG), 1-aminooxy-3-aminopropane, oxaliplatin, cisplatin, dicyclohexylamine, a derivative of any of the same, or a salt thereof.

14. The method according to any of claims 1 to 9, characterized in that the agent comprises a biofilm cation-depleting agent, optionally a cation exchange resin, an aminopolycarboxylic acid, a crown ether, an aza crown, or a cryptand.

15. The method according to claim 14, characterized in that the biofilm cation-depleting agent is from the group of: sulfonate, sulfopropyl, phosphocellulose, phosphocellulose P11, heparin sulfate or a derivative or analogue thereof.

16. A method for inhibiting the stability of a biofilm, characterized in that it comprises contacting the biofilm in vitro with an agent that interferes with the binding of a polyamine to DNA in the biofilm, wherein the contact comprises coating a surface Rcncrn / Lznza / YiAi 157 with an effective amount of cation-depleting agent, wherein the agent is not an HMGB1 protein, a fragment or an equivalent thereof.

17. A method for inhibiting the stability of a biofilm, characterized in that it comprises contacting the biofilm in vitro with an effective amount of an agent that interferes with the binding of a polyamine to DNA in the biofilm, wherein the contact comprises coating a surface with an effective amount of one or more cation-depleting agents, wherein the agent is not an HMGB1 protein, a fragment or an equivalent thereof.

18. The method according to any of claims 1 to 9 or 16 or 17, characterized in that the agent interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment.

19. The method according to any of claims 16 to 18, characterized in that the agent comprises an anti-B-DNA antibody or a fragment or derivative thereof.

20. The method according to any of claims 16 to 18, characterized in that the agent comprises riboflavin, ethidium bromide, bis(methidium) spermine, daunorubicin, TMPyP4, a quaternary benzo[c]phenanthridine alkaloid, quinacrine, 9-amino acridine or a derivative thereof.

21. The method according to any of claims 16 to 18, characterized in that the agent comprises chloroquine or a derivative thereof.

22. A method for inhibiting the stability of a biofilm, characterized in that it comprises contacting the biofilm in vitro with an effective amount of HMGB1 protein or a biologically active fragment thereof and anti-B-DNA antibody or a fragment or derivative thereof, wherein the contact comprises coating a surface with an effective amount of HMGB1 protein or a biologically active fragment thereof and anti-B-DNA antibody or a fragment or derivative thereof.

23. A method for inhibiting the stability of a biofilm, characterized in that it comprises contacting the biofilm in vitro with an effective amount of chloroquine and anti-B-DNA antibody or a fragment or derivative thereof, wherein the contact comprises coating a surface with an effective amount of chloroquine and anti-B-DNA antibody or a fragment or derivative thereof.

24. A method for treating a biofilm in a patient with systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF), characterized in that it comprises administering an effective amount of an agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment, wherein the agent is not an HMGB1 protein, a fragment, or an equivalent thereof. Rcncrn / Lznza / viAi 158 25. A method for treating a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF), characterized in that it comprises administering an effective amount of one or more agents that interfere with the conversion of B-DNA to Z-DNA in the biofilm or its local environment, wherein the agent is not an HMGB1 protein, a fragment or an equivalent thereof.

26. The method according to claim 22 or 25, characterized in that the agent comprises chloroquine or a derivative thereof.

27. The method according to claim 22 or 25, characterized in that the agent comprises an anti-B-DNA antibody or a fragment or derivative thereof.

28. The method according to claim 22 or 25, characterized in that the agent comprises riboflavin, ethidium bromide, bis(methidium)spermine, daunorubicin, TMPyP4, a quaternary benzo[c]phenanthridine alkaloid, quinacrine, 9-amino acridine or a derivative thereof.

29. A method for treating a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF), characterized in that it comprises administering an effective amount of HMGB1 protein or a biologically active fragment thereof and the anti-B-DNA antibody or a fragment or derivative thereof.

30. A method for treating a biofilm in a patient suffering from systemic lupus erythematosus (SLE) and / or cystic fibrosis (CF), characterized in that it comprises administering an effective amount of chloroquine and anti-B-DNA antibody or a fragment or derivative thereof.

31. A method for treating a biofilm that produces an infection related to the administration of platinum-based chemotherapy in a patient receiving or having received the chemotherapy, the method being characterized in that it comprises administering an effective amount of an agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment, wherein the agent is not an HMGB1 protein, a fragment or an equivalent thereof.

32. A method for treating a biofilm that produces an infection related to the administration of platinum-based chemotherapy in a patient receiving or having received the chemotherapy, the method being characterized in that it comprises administering an effective amount of one or more agents that interfere with the conversion of B-DNA to Z-DNA in the biofilm or its local environment, wherein the agent is not an HMGB1 protein, a fragment or equivalent thereof.

33. The method according to claim 31 or 32, characterized in that the agent comprises chloroquine or a derivative thereof. Rcncrn / Lznza / YiAi 159 34. The method according to claim 31 or 32, characterized in that the agent comprises an anti-B-DNA antibody or a fragment or derivative thereof.

35. The method according to claim 31 or 32, characterized in that the agent comprises riboflavin, ethidium bromide, bis(methidium)spermine, daunorubicin, TMPyP4, a quaternary benzo[c]phenanthridine alkaloid, quinacrine, 9-amino acridine or a derivative thereof.

36. A method for treating a biofilm that produces an infection related to the administration of platinum-based chemotherapy in a patient receiving or having received chemotherapy, the method being characterized in that it comprises administering an effective amount of HMGB1 protein or a biologically active fragment thereof and anti-B-DNA antibody or a fragment or derivative thereof.

37. A method for treating a biofilm that produces an infection related to the administration of platinum-based chemotherapy in a patient receiving or having received chemotherapy, the method being characterized in that it comprises administering an effective amount of chloroquine and anti-B-DNA antibody or a fragment or derivative thereof.

38. The method according to claim 1 or 5, characterized in that it further comprises contacting the biofilm with an effective amount of an agent that interferes with the binding of eDNA to a DNA-binding protein and / or an antibacterial agent.

39. The method according to claim 38, characterized in that the agent interfering with the binding of eDNA to a DNA-binding protein comprises one or more of an anti-DNABII antibody, an anti-IHF antibody and / or an anti-HU antibody, or fragments thereof.

40. The method according to any of claims 2-39, characterized in that it further comprises administering to the subject an effective amount of an agent that interferes with the binding of eDNA to a DNA-binding protein and / or an antibacterial agent.

41. The method of claim 40, characterized in that the agent interfering with the binding of eDNA to a DNA-binding protein comprises one or more of an anti-DNABII antibody, an anti-IHF antibody and / or an anti-HU antibody, or fragments thereof.

42. The method according to claim 14 or 15, characterized in that the biofilm cation-depleting agent has a net negative charge.

43. The method according to claim 14 or 15, characterized in that the biofilm cation-depleting agent has a net neutral charge. Rcncrn / Lznza / YiAi 160 44. The method according to claim 38, characterized in that the agent interfering with the binding of eDNA to a DNA-binding protein has a net negative charge.

45. The method according to claim 38, characterized in that the agent interfering with the binding of eDNA to a DNA-binding protein has a net neutral charge.

46. ​​The method according to claim 38, characterized in that the agent interfering with the binding of eDNA to a DNA-binding protein has a net positive charge.

47. The method according to any of claims 1 to 46, characterized in that the methods are performed in the absence of the administration of a DNase enzyme.

48. A composition characterized in that it comprises one, two or three or more of: an agent that interferes with the binding of a polyamine to DNA in the biofilm, an agent that depletes the cations of the biofilm, an agent that interferes with the conversion of B-DNA to Z-DNA in the biofilm or its local environment, an agent that interferes with the binding of eDNA to a DNA-binding protein and / or an antibacterial agent.

49. The composition according to claim 48, characterized in that it further comprises a pharmaceutically acceptable carrier.

50. The composition according to claim 48 or 49, characterized in that the agent interfering with the binding of a polyamine to DNA in the biofilm comprises one or more of: a polyamine analogue difluoromethylornithine, trans-4-methylcyclohexylamine, sardomozide, methylglyoxal-bis[guanylhydrazone] (MGBG), 1-aminooxy-3-aminopropane, oxaliplatin, cisplatin and / or dicyclohexylamine, a derivative of any of the same, or a salt thereof.

51. The composition according to claim 48 or 49, characterized in that it comprises one or more of: a cation exchange resin, an aminopolycarboxylic acid, a crown ether, an aza crown, or a cryptand, sulfonate, sulfopropyl, phosphocellulose, phosphocellulose R11 and / or heparin sulfate, or a derivative or analogue thereof.

52. The composition according to claim 48 or 49, characterized in that the agent interfering with the conversion of B-DNA to Z-DNA in the biofilm or its local environment comprises one or more of: HMGB1 protein, a fragment or equivalent thereof, an anti-B-DNA antibody or a fragment or derivative thereof, and / or chloroquine, or a derivative thereof.

53. The composition according to claim 48 or 49, characterized in that the agent interfering with the binding of eDNA to a DNA-binding protein 161 comprises one or more of an anti-DNABII antibody, an anti-IHF antibody and / or an anti-HU antibody, or fragments thereof.

54. A kit characterized in that it comprises the composition according to any of claims 48 to 53 and instructions for its use, and optionally in 5 where the agents are combined or packaged separately.

55. The kit according to claim 54, characterized in that the instructions for its use provide instructions for carrying out the method according to any of claims 1 to 47.