32results about "Polymyxins" patented technology

The invention belongs to the technical field of gene engineering, and particularly relates to a mutant of polymyxin efflux transporter and application of the mutant. The mutant is a PmxD transporter mutant, the amino acid sequence of the PmxD transporter mutant is shown as SEQ ID NO: 1, and compared with wild type PmxD, the polymyxin transport capacity of the PmxD transporter mutant (T38W) is improved by 450.46%; and the total discharge amount of polymyxin is increased by 85.72%. Meanwhile, the mutant can significantly improve the growth ability of the strain on a plate containing 250 [mu] g / mL of polymyxin B, namely significantly improve the autoresistance of paenibacillus polymyxa to polymyxin.

The invention provides novel pharmaceutical compositions of polymyxin B / trimethoprim and rifampin, as well as methods of their preparation and topical ophthalmic uses (e.g., treatment of ophthalmic infections).

A polyclonal antibody composition specifically binds the pTonB epitope (SEQ ID NO: 11) from Acinetobacter baumannii and is elicited by immunization with a multi-epitope antigen comprising thioredoxin leader, rigid linker, and kernels including SEQ ID NOs: 6, 7, 11, 12, and 8. These antibodies enhance opsonophagocytic killing of A. baumannii Ci79 via classical complement activation and Fey receptor-mediated phagocytosis by bone marrow-derived macrophages. Absorption of pTonB-specific antibodies reduces killing by >70%, confirming epitope dominance. Passive transfer of the composition protects >60% of mice in a lethal intranasal challenge model. Pharmaceutical compositions, treatment methods (alone or with antibiotics like colistin), prophylactic uses, diagnostic kits, and polyclonal compositions are disclosed for combating multidrug-resistant A. baumannii infections.

The present invention provides therapeutic compounds, such as compounds of formula I, or pharma- ceutically acceptable salts, hydrates or solvates thereof, pharmaceutical compositions thereof, methods of use thereof, and methods for making these compounds, as therapeutic or anti-cancer agents.

The present invention provides methods, compositions, and articles of manufacture useful for the prophylactic and therapeutic amelioration and treatment of gram-positive bacteria, and related conditions. The present invention provides compositions and methods incorporating and utilizing macolacin antibiotics or derivatives or variants thereof.

The invention provides polymyxin B sulfate and a preparation method thereof. According to the method, paenibacillus polymyxa is fermented in a liquid culture medium with wheat flour as a main carbon source and cottonseed cake powder and high-temperature soybean cake powder as main nitrogen sources to generate polymyxin B, and aluminum oxide is used as a chromatography medium to purify polymyxin B sulfate through a column chromatography process. Wheat peptone is added into the seed tank, so that growth of hyphae is facilitated, and the hyphae are full; the inoculation amount is reduced, and the seed expanding period is shortened. In the middle stage of fermentation, the amino acid mixed liquid is supplemented, so that the yield of the polymyxin B is increased, and specific impurities after the component B2 can be reduced. The quality of the product prepared by the method is obviously improved, the preparation method does not use an organic solvent and is green and environment-friendly, aluminum oxide can be regenerated and reused, and industrial production is facilitated.

Compositions and methods are provided for treating bacterial infections, including those that are challenging to treat by conventional medications, such as hospital acquired bacterial pneumonia (HABP), ventilator associated bacterial pneumonia (VABP), and bacteremia, caused by carbapenem-resistant bacteria such as Acinetobacter baumannii and Pseudomonas aeruginosa.

The application discloses a decapeptide derivative, a preparation method and application thereof. The application protects a Paenibacillus polymyxa, that is, Paenibacillus polymyxa CPCC 101223, and the preservation registration number is CGMCC No. 22854. The application also protects a preparation method of the compound, which comprises the following steps: fermenting and culturing the Paenibacillus polymyxa CPCC 101223 to obtain the compound. The application also protects application of the compound or a pharmaceutically acceptable salt thereof in preparation of a bacterial inhibitor. The application also protects the bacterial inhibitor, which contains the compound or the pharmaceutically acceptable salt thereof. The compound of the application is derived from the Paenibacillus polymyxa, has a simple preparation process, has good activity against gram-negative drug-resistant bacteria, provides a theoretical basis for clarifying the structure-activity relationship of the decapeptide antibacterial activity, and is suitable for research on a gram-negative drug-resistant bacteria leading compound or preparation of a gram-negative drug-resistant bacteria drug.

The present application provides a polymyxin prodrug compound with the structure shown in formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof. The polymyxin prodrug compound of the present application can effectively reduce the biological toxicity of polymyxin, selectively activate in bacterial infected tissues, achieve bacterial killing in infected sites, improve the bioavailability of polymyxin, achieve sustainable development and utilization of classic antibiotics, expand the scope of future clinical application of polymyxin, and has a broad clinical application prospect.

The application discloses a preparation method of polymyxin B sulfate impurity Z3 control product, and comprises the following steps: preparing a mobile phase, dissolving a sample containing polymyxin B sulfate, and then loading the sample into a chromatographic column, eluting the sample with the mobile phase, intercepting a fraction between a peak valley position of impurity B1-I and B1, and then re-loading and eluting the fraction to obtain a B1-I, Z3 and B1 triple peak after concentration, collecting a fraction corresponding to a peak part of Z3, repeatedly loading and eluting the fraction after concentration, and finally crystallizing to obtain a product Z3. The application has the advantages of simple operation, good separation effect and high-purity Z3 control product.

A novel 10 peptide capable of inhibiting the growth of bacteria that are resistant to existing polymyxin, a pharmaceutical composition comprising the novel 10 peptide, and an application thereof in the treatment or prevention of bacterial infections.

This application discloses a fluorescent probe for labeling the outer membrane of Gram-negative bacteria, its preparation method, and its application. The fluorescent probe uses polymyxin (with its hydrophobic tail and two amino acid residue pairs removed) as a targeting group specifically targeting the outer membrane of Gram-negative bacteria. This structure can specifically bind to the lipopolysaccharide structure in the outer membrane, and is then linked to the fluorophore rhodamine, which has switching properties, to design and synthesize a fluorescent dye. This fluorescent probe, possessing fluorescent switching properties, can be applied to super-resolution imaging of the outer membrane of Gram-negative bacteria.

This application provides therapeutic compounds, e.g., compounds of formula I, or pharma- ceutically acceptable salts, hydrates or solvates thereof that are therapeutic or anti-cancer agents, pharmaceutical compositions thereof, methods of use thereof, and methods of preparing these compounds.

The application relates to the technical field of coating preparation, in particular to a preparation method of a hydrophilic antibacterial hydrogel coating, which comprises the following steps: after acrylic acid, 4-acryloyloxybenzophenone, a thermal initiator, water and N,N,N',N'-tetramethyl ethylenediamine are mixed and react in the dark, a polymer solution with photo-reaction is obtained; the polymer solution is mixed with a zwitterionic monomer, a crosslinking agent and water to obtain a coating liquid; a substrate is treated with 10wt% 4-acryloyloxybenzophenone organic solvent for 5-10 minutes, the obtained coating liquid is coated on the surface of the substrate, is cured under ultraviolet light, is immersed in water to remove unreacted substances, and a hydrophilic hydrogel coating is obtained; the obtained hydrophilic hydrogel coating is immersed in a 2-(N-morpholine)ethanesulfonic acid (MES) solution containing 0.4M EDC and 0.1M N-hydroxysuccinimide (NHS) to perform activation treatment; colistin sulfate is added into the above MES solution to perform activation treatment, and a hydrophilic antibacterial hydrogel coating is obtained.

The present invention provides a combination antibiotic therapy for treating A. baumannii infections in a subject. The combination therapy includes rifabutin, and members of the polymyxin class of antibiotics such as, for example, commercially available natural product antibiotics such as polymyxin B and polymyxin E (colistin and its prodrug colistin methanesulfonate (CMS)), and synthetic or semi-synthetic derivatives and analogs such as, for example, SPR206, MRX-8, and QPX9003, and polymyxin-like antibiotics such as, for example, Po17306.

The invention provides a polymyxin compound of formula (1) and salts, solvates and protected forms thereof, pharmaceutical compositions comprising the compounds of formula (1), and the use of the compounds and compositions in methods of treatment, such as methods for the treatment of microbial infections. The compounds of formula (1) are represented thus:wherein —R15 is a group:and —R16 is hydrogen; —R17 is hydrogen -L- is a covalent bond or methylene; and —Ar is optionally substituted aryl. The groups —X—, —R1, —R2, —R3, —R4, and —R8 are as defined herein.

The present invention discloses a cyclopeptide glass and a pharmaceutical composition glass containing a cyclopeptide. The cyclopeptide glass of the present invention can exert both the effect of a drug and the function of a drug adjuvant, and compared with crystals and conventional pharmaceutical dosage forms and adjuvants, it can effectively accelerate the dissolution rate of a drug and improve the bioavailability of a drug, and is widely applied in the fields of drug delivery and sustained release, such as antitumor, antiviral, antibacterial, blood sugar control, immunoregulation, and neuroregulation.

The invention relates to novel compounds with the ability to link an immune response to a pathogen, to the use of said compounds in a disease or disorder mediated and / or caused by an infective agent, to compositions containing said compounds, processes for their preparation and to novel intermediates used in said process.

The application provides a polymyxin secretion engineering strain and a construction method and application thereof, and belongs to the technical field of biotechnology. One of the purposes of the application is to provide a polymyxin synthesis engineering strain, and the second purpose is to provide a polymyxin secretion model. In the application, a polymyxin synthesis gene cluster is expressed by using an exogenous inducible promoter in P. polymyxa, and a chassis cell is constructed; the chassis cell is used as a starting strain, and an efflux transporter gene pmxC and pmxD are knocked out, so that a polymyxin efflux down-regulation type chassis cell is constructed; a recombinant vector containing the gene pmxD is back-supplemented in the polymyxin efflux down-regulation type chassis cell, and the expression of pmxD is started by using a pathogenic bacterium-biased endogenous promoter. In this way, an engineering strain for intensively secreting polymyxin by exogenous induction of pathogenic bacteria can be obtained.

Antimicrobial peptide compounds, pharmaceutical compositions, and methods for their use in inhibiting microbial growth are provided. The methods provided include methods for inhibiting pan drug resistant Acinetobacter baumannii by administering the peptide compounds to a subject. A method is provided for inhibiting pan drug resistant Acinetobacter baumannii with a synergistic combination of peptide compound Acetyl-AS-aib-LRKL-aib-KRLL-amide (SEQ ID NO: 1) and polymyxin B. In other methods, peptide compounds are provided for inhibiting P. gingivalis which is the keystone bacteria of periodontal disease, the 6th most common infectious disease worldwide.

The application belongs to the technical field of microbial medicine, and particularly discloses a preparation method of a fermentation liquor with improved content of effective components of polymyxin B. The fermentation process is precisely controlled by adding carnosine as a key substance, adding glucose, designing a culture medium formula, and controlling temperature and pH in stages, so that the fermentation unit and the content of effective components are effectively improved, and thus the quality of the fermentation liquor is improved. Compared with a control example, the fermentation unit and the content of effective components are obviously improved, the fermentation unit is increased by 29.42% at most, and the effective components are increased by 12.32%.

The application discloses a kind of deuterated antibacterial peptide and its composition and application, belong to biological medicine field.The application is formed by introducing deuterated 2-amino butyric acid to form cyclic structure, and the affinity of antibacterial peptide to bacterial membrane is greatly improved compared with traditional drug (polymyxin B, D50) by combining with deuterium modification, and the selectivity of mammalian membrane is more than 884 times higher than that of control 884;The minimum bacteriostatic concentration of gram-negative bacteria in vitro is as low as 0.015 μg / mL, which is 67 times higher than polymyxin B, 33-67 times higher than D50 control peptide, about 17 times higher than non-deuterated antibacterial peptide 5, realizes efficient bacteriostasis at very low concentration;And human kidney cell toxicity is very low, and biological safety is better.In various infection models, its therapeutic effect is significantly better than the above three kinds of controls, and can be used for preparing anti-infection drugs, to provide "high efficiency and low toxicity" new scheme for clinical anti-infection treatment, and is suitable for the prevention and treatment of various infections.

The invention relates to the field of microorganisms, and discloses application of bacillus polymyxa and L-gamma-diaminobutyric acid in production of polymyxin B and a method for producing the polymyxin B. According to the method, through the synergistic effect of the bacillus polymyxa and the L-gamma-diaminobutyric acid, the yield of the polymyxin B is remarkably increased, non-target byproducts are reduced, and the large-scale production of the high-purity polymyxin B in medicine and animal husbandry is met.

A cyclic basic lipopeptide compound, and a preparation method therefor and a use thereof. The compound has a structure represented by general formula I, wherein AA represents amino acid. The preparation method for a cyclic lipopeptide compound comprises the following steps: (1) reacting an Fmoc-AA-OP side chain free amino group of a protected basic amino acid with a halogenated resin to obtain Fmoc-AA-OP-resin; (2) coupling Fmoc-AA-OP-resin one by one to obtain a linear polypeptide-resin; (3) selectively removing a protective group from the linear polypeptide-resin and carrying out solid-phase cyclization on the linear polypeptide-resin to obtain a cyclic polypeptide-resin; (4) carrying out acidolysis and ether precipitation on the cyclic polypeptide-resin to obtain a cyclic polypeptide crude product; and (5) carrying out purification and / or salt conversion and lyophilization on the cyclic polypeptide crude product to obtain a cyclic polypeptide pure product. The cyclic lipopeptide compound can be used for preparing antibacterial drugs, and particularly used for preparing antibacterial drugs having improved antibacterial activity and reduced renal toxicity, comprising an antibacterial drug against carbapenem drug-resistant "super bacteria". R0-CO-AA1-AA2-D / L-AA3-ring(4-10)[Dab4-AA5-D / L-AA6-AA7-AA8-AA9-AA10] I.

The present invention provides therapeutic compounds of formula I, which are therapeutic or anti-cancer agents: [Case 1] TIFF2026502619000119.tif54160 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, pharmaceutical compositions containing them, methods of using them, and methods for preparing these compounds are provided.

A novel decapeptide capable of inhibiting the growth of bacteria having drug resistance to existing polymyxin, a pharmaceutical composition comprising the novel decapeptide, and a use thereof in the treatment or prevention of bacterial infection.

The invention discloses a fermentation method for increasing the yield of polymyxin B. The fermentation method comprises the following steps that 1, bacillus polymyxa is inoculated into an initial culture medium containing Mg < 2 + > and Mn < 2 + > for fermentation, the concentration of Mg < 2 + > in the culture medium is 0.5-10 mM, and the concentration of Mn < 2 + > in the culture medium is 5-100 mu M; and step 2, sampling the fermentation liquor at set intervals, measuring the concentration of Mg < 2 + > / Mn < 2 + >, and supplementing a concentrated solution containing Mg < 2 + > and / or Mn < 2 + > into the fermentation liquor when the concentration of Mg < 2 + > is lower than a first threshold value and / or the concentration of Mn < 2 + > is lower than a second threshold value, so that the concentration of Mg < 2 + > in the fermentation liquor is maintained at 0.5-10mM, and the concentration of Mn < 2 + > is maintained at 5-100mu M. In the fermentation process of paenibacillus polymyxa, the concentration, the proportion and the adding time sequence of Mg < 2 + > and Mn < 2 + > ions in the culture medium are accurately controlled and optimized, the maximum catalytic efficiency of an NRPS enzyme system is met, and therefore synthesis of polymyxin B is efficiently driven.

The invention provides a polymyxin compound of formula (I) and salts, solvates and protected forms thereof, pharmaceutical compositions comprising the compounds of formula (I), and the use of the compounds and compositions in methods of treatment, such as methods for the treatment of microbial infections. The compounds of formula (I) are represented thus:wherein —R15 is a group:and —R16 is hydrogen; —R17 is hydrogen; -L- is a covalent bond or methylene; and —Ar is optionally substituted aryl. The groups —X—, —R1, —R2, —R3, —R4, and —R8 are as defined herein.