Use of quorum quenching (QQ) compounds for avoiding the formation of biofilms, biofouling or biocorrosion on surfaces

Abstract

The present invention relates to a coating composition and the use of one or more quorum quenching (QQ) compounds, selected from the group consisting of phenylethylamides, tryptamides, xenofuranones, xenocoumacines, prexenocoumacines, amicoumacines, preamicoumacines and / or PAX peptides for avoiding the formation of biofilms, biofouling or biocorrosion on surfaces. The present invention also relates to a method for avoiding the formation of biofilms, biofouling or biocorrosion on a surface.

Description

[0001] Title: Use of quorum quenching (QQ) compounds to prevent the formation of biofilms, biofouling, or biocorrosion on surfaces Description: Technical field: The present invention relates to the use of quorum quenching (QQ) compounds and methods for preventing the formation of biofilms, biofouling, or biocorrosion on surfaces, as well as coating compositions designed therefor, which comprise one or more such quorum quenching (QQ) compounds. State of the art: Quorum sensing (QS) is a regulatory system that regulates the behavior of microbial populations by detecting the concentration of signaling molecules spontaneously produced and released by bacteria. QS is thus directed at a cell density-based communication process in bacterial communities in which the expression of various target genes is activated or inactivated above a certain cell density.The strategy of blocking the QS system and inhibiting the production of virulence factors is called quorum quenching (QQ). This strategy attenuates virulence without killing the pathogens, thereby weakening the selective pressure on the pathogens and delaying the development of QQ-mediated resistance. QQ-driving molecules can reduce or even completely inhibit the production of virulence factors (including biofilm formation). QQ compounds can occur naturally or be developed and synthesized using chemical engineering. Many of the characterized QQ substances are enzymes with the ability to degrade signaling molecules. They can also interfere with cellular signaling cascades. In recent years, there have been significant theoretical and practical developments in the field of QS and QQ.Particularly in the development and use of marine resources, it has been found that marine microbial species are regulated by these two mechanisms. Although many QQ bacteria have been isolated from the marine environment, only a few of them are native plant isolates. Many of these bacteria produce QQ compounds, the effects of which, for example, on the formation of biofilms, have hardly been studied at all. Biofilms are formed by bacteria and other microorganisms and are exposed to specific environmental conditions (Costerton et al., 1994; Costerton et al., 1995). In a biofilm, bacteria can colonize different surfaces alone or together with other microorganisms (Hall-Stoodley et al., 2004; Flemming et al., 2016). In this process, a resistant mucous-like matrix is ​​produced, which surrounds the microorganisms and makes them very invulnerable. A biofilm in the human body, which, for example,Biofilms that colonize the lungs are more resistant to the body's defenses than individual cells, which requires higher doses of antibiotics (Bryers et al. 2008; Fleming et al. 2017). Biofilm formation is also one of the mechanisms regulated by quorum sensing systems (Ng & Bassler, 2009). In addition, many areas of our lives are negatively affected by biofilms on a daily basis, especially when they occur on surfaces in clinical facilities or in industry, such as in fluid-carrying hoses or pipes (Flemming, 2002; Forde et al., 2005). Biofilms are also the cause of biofouling, i.e., when impairments arise due to biofilm formation (Dang & Lovell, 2016; de Carvalho, 2018; Flemming, 2020). In clinical settings, biofilms on medical devices such as catheters and implants can cause problematic infections due to the colonization of pathogenic bacteria and fungi.It is estimated that approximately 65% ​​to 80% of microbial infections in humans are due to the formation of biofilms (Vickery et al., 2004; Jamal et al., 2018). In drinking water supply systems, biofilms and the associated biofouling can contaminate fresh water and corrode water pipes (Wingender & Flemming, 2004; Prest et al., 2016). Membranes used to filter drinking water can prevent contamination, but they can become heavily overgrown with microorganisms and thus lose quality, so that this type of filter must be replaced frequently (Ridgway et al., 1983). In the food industry, bacterial surface colonization can cause health problems and contamination, and biofouling can shorten the service life of the equipment used (Gule et al., 2016). In marine areas, such asBiofilms and biofouling are a major problem in the shipping industry, for example. Due to growth on ship hulls, fuel consumption increases exponentially due to the increased frictional resistance of these ships. Furthermore, biofilms contribute to the degradation of protective coatings on port facilities and ships, so that biocorrosion increases rapidly (Schultz, 2007; Munk & Kane, 2009). State-of-the-art solutions for preventing or removing biofilms or biofouling can be classified into physical or mechanical, chemical, and biological approaches (Flemming, 2020). In the shipping industry, physical or mechanical anti-fouling measures include, for example, the dewatering of ships and the mechanical removal of biofouling in a dry dock using chemical agents, or alternatively, the use of vacuum robots for underwater operations (Coutts et al., 2010).Ultrafiltration is also commonly used in drinking water supplies. Another physical or mechanical approach is the use of specific surfaces to circumvent mechanical cleaning. This involves smoothing the surfaces to such an extent that it becomes more difficult for organisms to adhere to them. This is usually done using electropolishing, a method also frequently used in the food industry (Jullien et al., 2003; Whitehead & Verran, 2009). Another physical approach to reduce biofouling is the use of ultrasound (Legg et al., 2015). Further options include the use of hydrophobic or hydrophilic surfaces to counteract biofouling (Genzer & Efimenko, 2006; Vladkova, 2009). This also includes the strategy of making use of the so-called lotus effect to prevent the attachment of microorganisms (Barthlott & Neinhuis, 1997).Another option for preventing biofouling is the use of special surfaces coated with titanium dioxide. These are activated by UV light to subsequently act as photocatalysts and kill the bacteria (Sunada et al., 1998). Self-polishing copolymer coatings are also widely used in the mechanical sector (Lewis, 2009). These coatings gradually detach from the surface, allowing the overgrown areas to repeatedly peel off, thus freeing the surface of biofouling (Dafforn et al., 2011). Tributyltin compounds can be added to these self-polishing copolymer coatings. These have a biocidal effect on all microorganisms (Lewis, 1998). Another biocidal additive in self-polishing coatings is the element copper (Nichols, 1988).However, non-biocidal compounds are also used in such self-polishing coatings. These are often silicone elastomers (Hellio et al., 2009). There are also various chemical strategies and solutions on the market to prevent biofilms and biofouling, although these have many disadvantages and limitations. One possibility is the use of acid on the overgrown surfaces (Parkar et al., 2004). Another option is to coat the affected surfaces with different copolymers. For example, amphiphilic or polyether-polyamide polymers are used. These variants of the anti-fouling strategy are primarily used on reverse osmosis membranes (Louie et al., 2006; Bucs et al., 2014). Another application to prevent biofouling is the use of special synthetic polysaccharides, which are intended to prevent the adhesion of microorganisms.This control variant is used on reverse osmosis membranes (Rendueles et al., 2013; Son et al., 2018). However, biocides are also used, which are initially applied to the desired areas or are only formed on the specific surfaces (Hüttinger, 1988; Jain et al., 2016; Wood et al., 2016). These are often fungicides and herbicides, such as dichlofluanid, Irgarol 1051, dichlorooctylisothiazolin, and diuron (Voulvoulis et al., 1999; Boxall et al., 2000; Thomas, 2001; Thomas, 2009). Furthermore, disinfectant solutions, such as ANOSAN TW, are used in drinking water systems to prevent biofilm formation and biofouling. In the biological field, the methods are based on blocking or inhibiting the QS mechanism of bacteria (Campouris et al., 2018; Iqbai et al., 2018; Mukerjee et al., 2018).Other strategies include the use of natural anti-fouling substances produced by microorganisms such as bacteria and microalgae (Sateesh et al., 2016; Cepas et al., 2019). These involve modifying surfaces to mimic realistic situations by incorporating these anti-fouling substances into the surface (Yu et al., 2011) and using bionic methods by copying and then applying biological surfaces such as shark skin from nature (Pu et al., 2016). Further strategies go so far as to directly use microorganisms with proven anti-fouling activities to combat biofouling (Dobretsov et al., 2013; Satheesh et al., 2016; Wood et al., 2016). Furthermore, enzymes are used that have proven anti-fouling activity and are immobilized on surfaces (Olsen et al., 2009; Petrova & Sauer, 2016).WO 2013 / 126814 A1 discloses indole derivatives for biofilm inhibition obtained from bacterial isolates of coral reef fish. Furthermore, the biosynthesis and function of amides in Xenorhabdus doucetiae and their quorum quenching activity against various bacterial quorum sensing systems are known (Bode E et al., 2017). The strategies and solutions mentioned above have various disadvantages and limitations. The dry-docking approach, which is very commonly used on ships to mechanically remove biofilm growth (Coutts et al., 2010), has the disadvantage of rendering the entire ship unusable for a certain period of time, which in turn incurs costs due to downtime and cleaning. The use of ultrafiltration systems, for example, in drinking water supply systems, also has certain disadvantages.Once biofouling occurs on ultrafiltration systems, these filters must be replaced because the desired water filtration quality is no longer guaranteed. This also results in high costs. In the food industry, surfaces smoothed by electropolishing are often used (Jullien et al., 2003; Whitehead & Verran, 2009). However, these do not prevent the growth of all abiotic particles, which then make the smoothed surfaces accessible to microorganisms. After the microorganisms adhere and subsequently produce the slime-like matrix, the smooth surface no longer exists after a certain period of time, which can then lead to biofouling. The approach of removing biofouling from the overgrown surfaces using ultrasound (Legg et al., 2015) also has limitations.Compatible materials must be used for this method; not all materials are generally suitable for ultrasound treatment. Furthermore, not all microorganisms form the same dense biofilm, which is why the frequency of the ultrasound must be varied to clean the entire surface. The use of hydrophobic or hydrophilic surfaces (Genzer & Efimenko, 2006; Vladkova, 2009) can lead to the adhesion of abiotic particles to the surface, thus weakening the desired effect on biofilm formation. Another disadvantage of using such surfaces is the generally low stability of the hydrophobic or hydrophilic coatings. The use of the so-called lotus effect (Barthlott & Neinhuis, 1997) also has disadvantages, as maintaining the lotus effect is not always easy or feasible.In addition, such surfaces are often susceptible to surfactants, which makes maintenance significantly more difficult (Flemming, 2020). Special surfaces coated with titanium dioxide do not ensure that the dead biomass is actually removed. Self-polishing coatings, which are intended to counteract the problem of dead biomass by gradually detaching from the surface, are problematic for the environment and health. Due to the fact that biocidal additives such as tributyltin or copper compounds are incorporated into these self-polishing coatings (Nichols, 1988; Lewis, 1998), these toxic compounds gradually enter the aqueous environment and pose a threat to the environment and human health (Wade et al., 2004; Trefry et al., 2008; Dafforn et al., 2011). Special, non-biocidal compounds, such asSilicone elastomers incorporated into such self-polishing coatings (Townsin & Anderson, 2009) also have disadvantages. For these to be effective against biofouling, certain speeds or pressures must be reached so that the coatings detach spontaneously. If this cannot be guaranteed, mechanical cleaning as described above is necessary. Chemical-based biofouling solutions are problematic because they are based on acids (Parkar et al., 2004). These include, for example, the use of the correct acid concentration, the correct temperature, and also the properties of the surface materials used (Flemming, 2020). Chemical action methods already used on reverse osmosis membranes, such as the immobilization of amphiphilic polymers or polyether-polyamide polymers (Louie et al., 2006; Bucs et al., 2014), or the use of synthetic polysaccharides (Rendueles et al., 2013; Son et al., 2018) have disadvantages. The stability and long-term efficacy of the products are questionable for the various polymers. The spectrum of activity of synthetic polysaccharides, on the other hand, is partly undefined and therefore questionable. Prevention of biofouling cannot therefore be guaranteed. Chemical biocides such as herbicides and fungicides (Voulvoulis et al., 1999; Boxall et al., 2000; Thomas, 2001; Thomas, 2009), which are immobilized on various surfaces to combat biofouling (Hüttinger, 1988; Jain et al., 2016; Wood et al., 2016), have disadvantages and even risks. Due to the release of biocides into the aqueous environment, these processes pose a risk to the environment and human health (Martinez & Barcelo, 2001; Reitsema, 2008). Furthermore, such methods can kill microorganisms, but cannot remove existing biofilm growth.Chemical disinfectant solutions used in drinking water systems to inhibit biofilms also have disadvantages. While these kill the microorganisms on the top layer of the fouling, they do not kill the organisms located further down or at the base of the biofilm. Biofilms are resilient and envelop the microorganisms with a protective, slimy matrix (Bryers et al., 2008; Fleming et al., 2017). As a result, biofouling in the drinking water system recurs shortly after the application of such a chemical treatment. The method of suppressing or blocking the quorum sensing system in microorganisms (Campouris et al., 2018; Iqbai et al., 2018; Mukerjee et al., 2018) or using natural anti-fouling substances (Sateesh et al., 2016; Cepas et al., 2019) may have certain disadvantages in terms of costs.This affects both long-term efficiency and thus also the resulting production costs. Further problems can arise from microorganisms whose biofilm formation is not influenced by the applied quorum quenching strategy. The direct use of microorganisms that exhibit anti-fouling activity carries the risk that they will be overgrown or even attacked by other organisms. Finally, the use of anti-fouling enzymes is highly questionable, as this process also entails disadvantages in terms of cost and functionality. The production costs for this process are very high. Furthermore, the stability of enzymes on surfaces is low, thus preventing long-term activity. Description of the invention: Against this background, the object of the present invention is to provide alternative compounds that are suitable for preventing the formation of biofilms, biofouling, or biocorrosion on surfaces.This object is achieved by one or more quorum quenching (QQ) compounds selected from the group consisting of phenylethylamides, tryptamides, xenofuranones, xenocoumacins, and / or peptide-antimicrobial-Xenorhabdus (PAX) peptides. The QQ compounds according to the invention, selected from the group consisting of phenylethylamides, tryptamides, xenofuranones, xenocoumacins, prexenocoumacins, amicoumacins, preamicoumacins, and / or PAX peptides, have in common that they are secondary metabolites subject to the QQ mechanism and produced by entomopathogenic bacteria. Surprisingly, it has been shown that the QQ compounds according to the invention prevent bacterial biofilms and thus also biofouling and biocorrosion on any surface, or at least delay their development. This effect was unexpected.Preferably, the QQ compounds according to the invention, i.e., phenylethylamides, tryptamides, xenofuranones, xenocoumacins, prexenocoumacins, amicoumacins, preamicoumacins, and / or PAX peptides, are obtained from entomopathogenic bacteria of the genus Photorhabdus and Xenorhabdus. Unlike other biological or chemical biocides used for biofilm prevention or removal, the QQ compounds according to the invention exhibit no known disadvantages or toxicity. Furthermore, the QQ compounds according to the invention are also sustainable, i.e., they are capable of preventing or avoiding the formation of resistant biofilms, thus preventing the recurrence of biofilms and the associated biofouling or biocorrosion.Due to their broad-spectrum activity, the substances according to the invention are more flexible in their application and more cost-effective to produce than the physical-mechanical, chemical, or biological approaches known from the prior art. Finally, they pose no risk to the environment or human health because they are based on non-biocidal mechanisms. The anti-biofilm and anti-biofouling effect of the QQ compounds according to the invention is presumably due to the quorum sensing (QS) mechanism, so that the surprising active principle of the present invention is based on quorum quenching. Due to the quorum quenching properties of the QQ compounds according to the invention, it is possible to inhibit quorum sensing, i.e., communication between bacteria. Since biofilms only develop as a result of communication between bacteria, biofilm formation is inhibited in the presence of the QQ compounds according to the invention.Biofouling or biocorrosion can therefore no longer occur, since the basis for biofouling or biocorrosion requires bacterial biofilm formation. Due to their structure, the QQ compounds according to the invention can be incorporated onto different surfaces as well as in various compositions. The compounds according to the invention are preferably components of varnishes, paints, or impregnating agents. Surfaces can be treated by coating, spraying, brushing, or in other ways. The invention is not limited to a specific type of treatment and encompasses all common methods for treating surfaces. The structures of the QQ compounds according to the invention are based on the basic compounds shown below: Table 1: # QSI QSI C v HH102 Mw R 1a++*** 2051b + 1 + 2 3 + 4 - 5 - 6 261 7 27110 - - 303 11 329 12 343 13 - - 331 14 355 15 357 16 381 1 7 - - 383 18 - - 359 19 - - 385 20 387 Particularly preferred phenylethylamides for removing biofilms or preventing biofouling and biocorrosion are compounds 8 to 10 according to Table 1, based on the following basic structure: where R = alkyl or aryl (see Tables 1 and 2 for representative examples). Preferred tryptamides that can be used in the present invention are the QQ compounds from Xenorhabdus doucetiae (Bode et al. 2017) listed in Table 2 below. Table 2: R 22 + - 272 23 - - 286 24 300 25 314 26 326 27 328 28 340 29 (+)* - 342 30 345 31 368 32 370 33 422 34 - - 398 35 - - 424 36 - - 426 37 452 A particularly preferred tryptamide for use in removing biofilms or preventing biofouling and biocorrosion is compound No. 22 according to Table 2, based on the following basic structure: where R = alkyl or aryl (see Tables 1 and 2 for representative examples) Preferred xenofuranones that can be used in the present invention for removing biofilms or preventing biofouling and biocorrosion are given by (2) O OH HOOO OH m / z 283.1 O C17H15O4 m / z 283.1 C17H15O4 m / z 267.1 m / z 325.1 CHO C19H17O5 17 15 3 (5) 10 OO OH O (7) HO O OOO OH The preferred xenofuranones of the present invention have the following basic structure. 2 where R 1 = H or OH; R 2= H or OH; R 3 = H, -COOCH3, -COO(CH2)3CH3, -COOH or -COOCH3; R 4 = H or -CH3. Table 3 summarizes the compounds 1 to 8 preferred for the invention for removing biofilms or preventing biofouling and biocorrosion, along with their respective structures and properties. Table 3: Preferred xenocoumacins that can be used in the present invention are those listed in Table 2 below from Xenorhabdus doucetiae (Bode E et al. 2017). Preferred xenocoumacins of the present invention are xenocoumacin-1 (1) and xenocoumacin-2 (2). Furthermore, the prexenocoumacins AE (3-7), which are also included, can also be effectively used in the methods of the invention. An alternative embodiment utilizes amicoumacins or preamicoumacins, which are based on the following structures and are produced by Xenorhabdus bovienii (Park et al., 2016).

[0002] The preamicoumacins used according to the invention are prodrugs that comprise an N-acyl-D-Asn residue. Preferred PAX peptides of the invention are based on the following basic structure. where A = butylamine B = propylguanidine R = (3R,7Z)-3-hydroxytetradec-7-enoyl, (3R)-3-hydroxytetradecanoyl, (3R)-3-hydroxypentadecanoyl, (3R,9Z)-3-hydroxyhexadec-9-enoyl, (3R)-3-hydroxyhexadecanoyl, (3R,10Z)-3-hydroxyheptadec-10-enoyl, (3R)-3-hydroxyheptadecanoyl, (3R,11Z)-3-hydroxyoctadec-11-enoyl, or any fatty acid (saturated / unsaturated, hydroxylated / non-hydroxylated, iso-branched / linear, or a combination thereof). Preferred PAX peptides of the present invention are listed in Table 4 below. Table 4: No. Name A / BR 1 PAX5 A (3R,7Z)-3-hydroxytetradec-7-enoyl 2 PAX1' A (3R)-3-hydroxytetradecanoyl 3 PAX3' A (3R)-3-hydroxypentadecanoyl 4 PAX6 B (3R,7Z)-3-hydroxytetradec-7-enoyl 5 PAX2' B (3R)-3-hydroxytetradecanoyl 6 PAX7 A (3R)-3-hydroxyhexadecanoyl 7 PAX4' B (3R)-3-hydroxypentadecanoyl 8 PAX8 A (3R)-3-hydroxyoctadecanoyl 9 PAX9 B (3R,9Z)-3-hydroxyhexadec-9-enoyl 10 PAX10 B (3R)-3-hydroxyhexadecanoyl 11 PAX11 B (3R,10Z)-3-hydroxyheptadec-10-enoyl 12 PAX12 B (3R)-3-hydroxyheptadecanoyl 13 PAX13 B (3R,11Z)-3-hydroxyoctadec-11-enoyl. In particularly preferred QQ compounds, the PAX peptides comprise (3R)-3-hydroxytetradecanoyl for A and (3R)-3-hydroxytetradecanoyl for B (compounds 2 and 5 from Table 4). The QQ compounds according to the invention can be used for the non-biocidal control of biofilms. Due to the composition and structure of the QQ compounds, surfaces treated in this way can be immobilized or impregnated with entrainers.The choice of material is therefore irrelevant. Since the QQ compounds according to the invention can be used in both hydrophobic and hydrophilic environments, it is possible that they can penetrate varnishes or paint layers. Therefore, the surface to be treated is preferably coated with a paint or impregnate containing phenylethylamides, tryptamides, xenofuranones, xenocoumacins, prexenocoumacins, amicoumacins, preamicoumacins, and / or PAX peptides, or mixtures of one or more of these components. In the present invention, it was demonstrated in the following examples that the QQ compounds described herein exhibited no toxicity toward bacteria or other microorganisms tested. It can therefore be assumed that the environment and human health are not adversely affected by the use of the QQ compounds.Surprisingly, even low concentrations of the QQ compounds according to the invention are sufficient to prevent biofilm formation or biofouling. This is presumably due to the quorum quenching effect. The QQ compounds according to the invention can be used either individually or in combination. Long-term effectiveness can be ensured when multiple secondary metabolites are used. The surfaces to be treated are preferably surfaces colonized by biofilm, such as those found on ships, drinking water pipes, or industrial process lines. The process lines are preferably pipelines in the food industry or biotechnology. It is envisaged that one or more QQ compounds are incorporated or applied onto or into a surface.The prevention of biofilm formation by the QQ compounds according to the invention prevents even higher organisms from adhering to the surfaces. This is a major advantage, particularly for ship hulls, as it prevents non-native organisms from being introduced into foreign waters, which could potentially affect or disrupt native marine flora or fauna. The invention also relates to a coating composition for treating surfaces to prevent the formation of biofilms, biofouling, or biocorrosion on a surface, wherein the composition contains one or more quorum quenching (QQ) compounds selected from the group consisting of phenylethylamides, tryptamides, xenofuranones, xenocoumacins, and / or PAX peptides. The composition is preferably a varnish, paint, or impregnate.The QQ compounds according to the invention offer the economic advantage of being very easy to produce biotechnologically. Due to known methods for obtaining these secondary metabolites from Photorhabdus or Xenorhabdus, scale-up to an industrial scale is also possible. The use of bioreactors, which allow for appropriate scaling, is preferred. The high efficiency and efficacy, and the associated low active concentrations, also reduce costs. The inexpensive production and handling, as well as the long-term efficacy and non-toxic effects, represent significant advantages of the invention.The invention further relates to methods for preventing the formation of biofilms, biofouling, or biocorrosion on a surface, characterized in that the surface is treated with a composition containing one or more quorum quenching (QQ) compounds selected from the group consisting of phenylethylamides, tryptamides, xenofuranones, xenocoumacins, prexenocoumacins, amicoumacins, preamicoumacins, and / or PAX peptides. Preferably, the method involves treating the surface with a mixture of at least two of the quorum quenching (QQ) compounds. Preferably, the mixture is a mixture of phenylethylamides and tryptamides. The phenylethylamides, tryptamides, xenofuranones, xenocoumacins, prexenocoumacins, amicoumacins, preamicoumacins and / or PAX peptides are preferably obtained from extracts of entomopathogenic bacteria of the genus Photorhabdus and Xenorhabdus.The xenocoumacin is preferably xenocoumacin-1 or xenocoumacin-2. The surface treated by the method is preferably a surface colonizable with a biofilm on ships, a surface in drinking water pipes or in process pipes, in particular process pipes in the food industry or biotechnology. In a preferred variant, one or a mixture of several QQ compounds is incorporated or applied onto or into a surface. In a further preferred variant, the surface colonizable with a biofilm is coated with a varnish, paint or impregnate containing phenylethylamides, tryptamides, xenofuranones, xenocoumacins, prexenocoumacins, amicoumacins, preamicoumacins and / or PAX peptides or mixtures of one or more of these components.In areas where the formation of biofilms requires the use of antibiotics, for example in medical fields, the invention helps to avoid the use of antibiotics or high doses. The treatment of fluid-carrying hoses or pipes leads to the prevention or at least significant reduction of biofilm formation via the QQ compounds according to the invention. This also prevents biofouling, in particular microfouling and macrofouling, i.e., the impairments caused by biofilm formation are prevented. In drinking water supply systems, pipes or drinking water lines can be treated with the QQ compounds according to the invention, thus preventing growth with microorganisms and thus the formation of biofilms. The use of the QQ compounds according to the invention is also suitable in the food industry for preventing bacterial surface colonization or biofouling.In the shipping sector, treating ship hulls with a mixture of the QQ compounds according to the invention helps prevent biofilms from forming in the first place, thus preventing damage to the protective coatings on the ship hulls. The addition of heavy metals or other biocidal metals to ship paints can be dispensed with. Instead, the QQ natural substances according to the invention are added as natural secondary metabolites. In ships, treatment with the QQ compounds according to the invention can complement or support the mechanical removal of biofouling. Subsequent treatment prevents subsequent growth of fouling on the ship's hull. The use of sometimes toxic, chemical, or biological methods can be dispensed with. The invention is explained in more detail in the following exemplary embodiments. However, the invention is in no way limited to these exemplary embodiments.The skilled person will recognize that the secondary metabolites described here can act individually or synergistically. Brief description of the figures: Fig. 1 shows the effect of the substance class phenylethylamide / tryptamide on the biofilm production of selected bacteria. Fig. 2 shows the effect of the substance class PAX peptides on the biofilm production of selected bacteria. Fig. 3 shows the effect of the substance class xenocoumacins on the biofilm production of selected bacteria. Fig. 4 shows the effect of the substance class xenofuranones on the biofilm production of selected bacteria. Fig. 5 shows the effect of the substance class phenylethylamide / tryptamide on the biofilm production of P. inhibens in undiluted and diluted form. Fig. 6 shows the effect of the substance class phenylethylamide / tryptamide on the biofilm production of S. pituitosa in undiluted and diluted form. Fig. 7 shows the effect of the substance class xenofuranones on the biofilm production of P.gallaeciensis after incorporation. Figure 8 shows the synergistic effect of the substance class phenylethylamide / tryptamide and xenofuranones on the biofilm production of S. pituitosa. Figure 9 shows the synergistic effect of the substance class PAX peptides and xenofuranones on the biofilm production of P. gallaeciensis. Figure 10 shows the effect of the substance class phenylethylamide / tryptamide on the biofilm production of P. aeruginosa after incorporation onto plastic surfaces (PP). The analysis was performed using crystal violet staining. Figure 11 shows the effect of the substance class phenylethylamide / tryptamide on the biofilm production of P. aeruginosa after incorporation onto plastic surfaces (polypropylene, PP). The analysis was performed using confocal fluorescence microscopy (CLSM). Figure 11A shows the pronounced formation of biofilm of P. aeruginosa on an uncoated plastic surface. In Fig.Figure 11B shows the significant reduction in biofilm formation on the surface coated with the QQ compounds (phenylethylamides / tryptamides). The QQ compounds were part of a coating composition that was applied to the surface. Figure 12 shows the effect of the selected pure substances from the phenylethylamide class (Table 1) on the biofilm formation of P. aeruginosa. In the control, only isopropanol was added, without the addition of the pure substances. Figure 13 shows the effect of the selected pure substance from the tryptamide class (Table 2) on the biofilm formation of P. aeruginosa. In the control, only isopropanol was added, without the addition of the pure substance. Figure 14 shows the effect of the selected pure substance (xenocoumacin-1) from the xenocoumacin class on the biofilm formation of P. aeruginosa. In the control, only isopropanol was added, without the addition of the pure substance.Figure 15 shows the effect of selected pure substances from the xenofuranones (Table 3) on biofilm formation by P. gallaeciensis. In the control, only isopropanol was added, without the pure substances. Best mode for carrying out the invention: Examples: To test the efficacy of the QQ compounds from the phenylethylamide and tryptamide classes, biofilm production was investigated with selected bacteria. Mixtures of phenylethylamides and tryptamides were used, with the proportion of phenylethylamides being greater than that of tryptamides. The results are summarized in Figure 1. B. diminuta served as a control, as no effect on biofilm formation was observed. The results show that the phenylethylamides and tryptamides used lead to a significant reduction in biofilm formation.Figure 2 shows the effect of QQ compounds from the PAX peptide class on the biofilm production of selected bacteria. B. diminuta served as a control, as no effect on biofilm formation was observed. Here, too, the PAX peptides were able to significantly reduce biofilm formation. In Figure 3, xenocoumacins were tested on the biofilm production of selected bacteria. B. diminuta also served as a control, but no effect on biofilm formation was observed. Biofilm formation was reduced by more than 50% in P. aeruginosa. Figure 4 shows the effect of the xenofuranones on the biofilm production of selected bacteria. Here, B. diminuta also served as a control, but biofilm production was reduced by more than 90% in certain bacteria. A similarly strong effect was also shown in the experiment with the effect of phenylethylamides / tryptamides on P.inhibens, the results of which are shown in Fig. 5. The effect of the phenylethylamides / tryptamides used on the biofilm production of P. inhibens was investigated in undiluted and diluted form. The sample containing no QQ compounds served as the control. A similar picture is shown with S. pituitosa, which is shown in Fig. 6. Here, too, the biofilm production of S. pituitosa was investigated in undiluted and diluted form using phenylethylamides / tryptamides as QQ compounds. The sample without the QQ compound served as the control. In Fig. 7, the effect of the QQ compounds of the substance class xenofuranones on the biofilm production of P. gallaeciensis was investigated in undiluted and diluted form. Here, too, the sample containing no QQ compounds served as the control. Biofilm formation was suppressed by more than 90%.Furthermore, the synergistic effect of several QQ compounds was investigated. In the experiment shown in Fig. 8, a combination of phenylethylamides / tryptamides and xenofuranones was used, and their synergistic effect on S. pituitosa with regard to biofilm formation was evaluated. The results show that synergistic administration of phenylethylamides / tryptamides and xenofuranones further reduces biofilm production compared to the individual compounds of the substance classes. The reduction was significantly less than 3% compared to the 100% control. A similar picture emerges from the combination of PAX peptides and xenofuranones, as shown in the experiments shown in Fig. 9. Here, the synergistic effect of PAX peptides and xenofuranones compared to the individual substance classes, i.e., PAX peptides and xenofuranones, is shown. Synergistic administration again significantly reduced biofilm production compared to the individual compounds.No addition of a QQ compound also served as a control. Furthermore, the effect of phenylethylamides / tryptamides on the biofilm production of P. aeruginosa was investigated after incorporation onto PP plastic surfaces. The analysis was performed using crystal violet staining. Almost no biofilm production was observed in the coating containing the QQ compounds according to the invention, whereas the plastic surface without QQ compounds was completely colonized with biofilms. These experiments clearly demonstrate that a coating composition containing one or more of the QQ compounds according to the invention can be effectively used as a surface coating (e.g., in the form of a varnish or paint) to prevent the formation of biofilms and thus to prevent biofouling or biocorrosion. The analysis of the plastic surfaces (uncoated) and QQ-coated) was shown in Fig.11 was further investigated using confocal fluorescence microscopy (CLSM). In the presence of QQ compounds in the coating composition, biofilm formation could be significantly reduced. In the experiments in Figures 12-15, pure substances were used to demonstrate their effect on biofilm formation. The effect of phenylethylamide, tryptamide, and xenofuranone pure substances on the biofilm formation of various bacterial strains is shown. The formation of biofilms caused by P. aeruginosa or P. gallaeciensis could be significantly reduced by treatment with the substances compared to the controls (without the addition of pure substances). The substances are therefore suitable for reducing or preventing the formation of biofilms and thus for preventing biofouling and biocorrosion. Materials and Methods: Bacterial strains and growth conditions. The bacterial strain B. licheniformis was used by the research group of Dr.The bacterial strain P. aeruginosa PA14 was provided by the group of Dr. Max Schobert (Technical University of Braunschweig, Germany). The bacterial strains B. subtilis (168), M. luteus, and S. salivarius were provided by the group of Dr. Kirsten Jung (Ludwig Maximilian University of Munich, Germany). The bacterial strains B. nasdae (DSM 100487), E. aurantiacum (DSM 6209), M. mesophilicum (DSM 1708), P. gallaeciensis (DSM 26640), P. inhibens (DSM 16374), S. adhaesiva (DSM 7418), S. mutans (DSM 20523), S. pituitosa (DSM 13101), R. maritimus (DSM 18849), S. aureus subsp. aureus (DSM 11823), S. epidermidis (DSM 28764), B. diminuta (DSM 7234), P. fluorescens (DSM 6147), H. aquamarina (DSM 4739), H. alkalilenta (DSM 17697) and G.mysorens (DSM 12798) were purchased from the German Collection of Microorganisms and Cell Cultures (DSMZ, Braunschweig, Germany). B. licheniformis and S. pituitosa were grown aerobically at 30°C in M1 medium (0.5% w / v soybean peptone, 0.3% w / v meat extract). B. nasdae, S. adhaesiva, S. aureus, and S. epidermidis were grown aerobically at 30°C in TSY medium (1.7% w / v tryptone, 0.3% w / v soybean peptone, 0.25% w / v glucose, 0.5% w / v NaCl, 0.25% w / v K2HPO4, 0.3% w / v yeast extract, pH 7.0). B. subtilis, M. luteus, P. aeruginosa, and P. fluorescens were grown aerobically at 30°C in LB medium (1% w / v NaCl, 1% w / v tryptone, 0.5% w / v yeast extract). E. aurantiacum, H. aquamarina, P. gallaeciensis, P. inhibens, R. maritimus, H. alkalilenta, and G. mysorens were grown aerobically at 30°C in 2216 medium (Thermo Fisher, Pittsburgh, USA).mesophilicum was grown aerobically at 30°C in M1 + 1% methanol medium (0.5% w / v soybean peptone, 0.3% w / v meat extract, 1% v / v MeOH). S. mutans and S. salivarius were grown microaerophilically (5% CO2) at 30°C in TSY medium. B. diminuta was grown aerobically at 30°C in CM3 medium (0.1% w / v meat extract, 0.2% w / v yeast extract, 0.5% w / v soybean peptone, 0.5% w / v NaCl). To cast agar plates, 1.5% w / v agar-agar (Carl Roth, Karlsruhe, Germany) was added to the respective medium. Biofilm induction of the individual bacterial strains. To form biofilm, overnight cultures of the bacteria were diluted in the corresponding biofilm-inducing media to an OD600 of 0.5. B. licheniformis, B. nasdae, and S.salivarius were grown in RS medium (0.025% (w / v) K2SO4, 1.012% (w / v) MgCl2x 6 H2O, 1% (w / v) glucose, 0.01% (w / v) casein hydrolyzate, 0.5% (w / v) yeast extract, 0.3% (w / v) Tris, 0.2% (v / v) trace element solution (0.04% (w / v) ZnCl2, 0.2% (w / v) FeCl3 x 6 H2O, 0.01% (w / v) CuCl2 x 2 H2O, 0.01% (w / v) MnCl2x 4 H2O, 0.01% (w / v) Na2B4O7x 10 H2O, 0.01% (w / v) (NH4)6Mo7O. 24 x 4 H2O), 0.1% (v / v) KH2PO4(0.5%), 0.04% (v / v) CaCl2(5M) ) to an OD 600 of 0.5. B. subtilis, M. luteus, P. aeruginosa, S. aureus, S. epidermidis and P. fluorescens were diluted in LB medium to an OD 600 of 0.5. E. aurantiacum, H. aquamarina, P. gallaeciensis, P. inhibens, R. maritimus and G. mysorens were diluted in 2216 medium to an OD 600 of 0.5. M. mesophilicum, S. adhaesiva, S. pituitosa, B. diminuta and H. alkalilenta were diluted in TSY medium to an OD 600Diluted by 0.5. Investigation of the QQ substances for their biofilm-inhibiting effect. The respective candidate substance classes of the QQ natural products produced by Photorhabdus and Xenorhabdus were provided by the research group of Dr. Helge Bode (Goethe University Frankfurt, Germany). The samples were culture supernatant and the QQ natural products produced therein. The experiment was carried out using 96-well microtiter plates (Sarstedt, Nuremberg, Germany). For this purpose, 20 µl of the respective substance class were pipetted into a microtiter plate well and air-dried under a sterile bench. Dilutions of the QQ natural products were prepared in sterile H2O. To demonstrate a synergistic effect, 20 µl of each candidate substance class was pipetted into the same well.After all liquid had evaporated, 50 µl of EtOH (70% v / v) was added to exclude possible bacterial contamination. The microtiter plate was then air-dried again in a laminar flow hood. Subsequently, 135 µl of the respective bacterial solution, which had previously been diluted in the corresponding medium to an OD600 of 0.5, was added to the QQ natural products. After incubation for 72 hours at 30°C under aerobic conditions (exceptions: S. mutans and S. salivarius, which were incubated microaerophilically), the biofilm was quantitatively examined. For this purpose, the microtiter plates were rinsed with distilled water after incubation to remove any bacteria that were not adhered to the surface. The microtiter plate was then air-dried upside down under a fume hood for 30 minutes.Finally, 135 µl of crystal violet solution (1% w / v) (Sigma-Aldrich, Darmstadt, Germany) was pipetted into the respective wells. The microtiter plates were then incubated at room temperature for 30 minutes. The plates were then rinsed twice with distilled water and then dried upside down under a fume hood for a minimum of six hours at room temperature. The cell-binding crystal violet was then dissolved in 135 µl of acetic acid (30% (v / v)) (Carl Roth, Karlsruhe, Germany). The microtiter plates were then read using a plate reader (Tecan, Crailsheim, Germany). For this purpose, the absorbance at 575 nm was measured. The obtained data were subsequently evaluated using Microsoft Excel. Investigation of the pure substances for their biofilm-inhibiting effect.All pure substances of the individual substance classes of the QQ natural products produced by Photorhabdus and Xenorhabdus were purified and provided by the research group of Dr. Helge Bode (Goethe University Frankfurt, Germany). Therefore, the samples are not mixtures of the substances, but rather a purified substance each, which can be assigned to the substance classes. The experiment was carried out using 96-well microtiter plates (Sarstedt, Nuremberg, Germany). For this purpose, the dried pure substances were resuspended in isopropanol (Carl Roth, Karlsruhe, Germany). Subsequently, 135 µl of the respective bacterial solution, which had previously been diluted to an OD in the corresponding medium, were added. 600of 0.5, was added to the individual wells of the microtiter plate. 1.35 μl of the pure substance was then added to achieve a final concentration of 4 nM. After incubation for 72 hours at 30°C under aerobic conditions, the biofilm was quantitatively examined. For this purpose, the microtiter plates were rinsed with distilled water after incubation to remove any bacteria that were not adhered to the surface. The microtiter plates were then air-dried upside down in a fume hood for 30 minutes. Finally, 135 μl of crystal violet solution (1% w / v) (Sigma-Aldrich, Darmstadt, Germany) was pipetted into the respective wells. The microtiter plates were then incubated at room temperature for 30 minutes. The plates were then rinsed twice with distilled water and then dried upside down in a fume hood for a minimum of six hours at room temperature.The cell-binding crystal violet was then dissolved in 135 µl of acetic acid (30% v / v) (Carl Roth, Karlsruhe, Germany). The microtiter plates were then read using a plate reader (Tecan, Crailsheim, Germany). For this purpose, the absorbance was measured at 575 nm. The obtained data were subsequently evaluated using Microsoft Excel. Investigation of QQ natural product activity after impregnation. To test the applicability of the QQ natural products, plastic plates were impregnated with QQ natural products (Fraunhofer UMSICHT, Oberhausen, Germany). Subsequently, a specially developed microfluidic system was used to simulate near-natural conditions. For this purpose, the plastic plates were placed in a specially developed flow cell (P cell). The P cells were then connected to a peristaltic pump (Athanasios Gazanis, JGU) and flushed with EtOH (70% (v / v)) at a rate of 100 ml / h.The P cells were then rinsed with 250 ml of sterile H2O at a rate of 100 ml / h to remove any remaining solvent. After decontaminating the microfluidic system, 5 ml of a diluted P. aeruginosa culture (LB medium, OD) was added. 600= 0.5) was injected into the P cell. To ensure bacterial adhesion to the platelet surface, the P cell was incubated for three hours at 30°C without flow. The P cell was then connected to LB medium and the flow rate was set to 5 ml / h using the peristaltic pump. After 72 hours of incubation, the platelets were removed and analyzed macroscopically and microscopically. Macroscopic analysis of the plastic platelets using crystal violet. After incubation in the microfluidic system, the platelets were removed from the P cell and rinsed with distilled water to remove any bacteria that did not adhere to the surface. The platelets were then placed in a 24-well microtiter plate (Sarstedt) and overlaid with 1 ml of crystal violet (1% w / v, Sigma Aldrich). Incubation was carried out for 30 minutes at room temperature.The slides were then rinsed twice with distilled water to remove unbound crystal violet. The slides were then air-dried for a minimum of six hours. The slides were then placed in a 24-well microtiter plate and overlaid with 1 ml of acetic acid (30% v / v). The dissolved crystal violet was quantified using a plate reader (Tecan). For this purpose, the absorbance at 575 nm was analyzed. The obtained data were evaluated using Microsoft Excel. Microscopic analysis of the plastic slides using confocal microscopy (CLSM). After incubation in the microfluidic system, the slides were removed from the P cell and rinsed with distilled water to remove any bacteria that did not adhere to the surface.The slides were then placed in a 24-well microtiter plate (Sarstedt), overlaid with 1 ml of a SYTO 9 and propidium iodide solution (Thermo Fisher Scientific), and incubated at 30°C for 30 minutes. The slides were then rinsed with H2O, air-dried, and mounted on microscope slides. The surface of the plastic slides was examined using an LSM 880 confocal microscope (Carl Zeiss, Jena, Germany). The SYTO 9 fluorophore was visualized using an argon laser at 488 nm. The propidium iodide fluorophore was visualized using a helium-neon laser at 543 nm. The resulting images were processed and finally analyzed using the ZEN black software.

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Claims

Claims:

1. A method for preventing the formation of biofilms, biofouling, or biocorrosion on a surface, characterized in that the surface is treated with a composition containing one or more quorum quenching (QQ) compounds selected from the group consisting of phenylethylamides, tryptamides, xenofuranones, xenocoumacins, prexenocoumacins, amicoumacins, preamicoumacins, and / or PAX peptides.

2. The method according to claim 1, characterized in that the surface is treated with a mixture of at least two of the quorum quenching (QQ) compounds.

3. The method according to claim 2, characterized in that it is a mixture of phenylethylamides and tryptamides. 4.Method according to claim 1, characterized in that the phenylethylamides, tryptamides, xenofuranones, xenocoumacins, prexenocoumacins, amicoumacins, preamicoumacins and / or PAX peptides are obtained from extracts of entomopathogenic bacteria of the genus Photorhabdus and Xenorhabdus.

5. Method according to claim 1, characterized in that the xenocoumacin is xenocoumacin-1 or xenocoumacin-2.

6. Method according to claim 1, characterized in that the surface is a surface colonizable with a biofilm in ships.

7. Method according to claim 1, characterized in that the surface is a surface colonizable with a biofilm in drinking water pipes.

8. Method according to claim 1, characterized in that the surface is a surface colonizable with a biofilm in process pipes.Method according to claim 1, characterized in that the surface is a surface colonizable with a biofilm in process lines of the food industry.

10. The method according to claim 1, characterized in that the surface is a surface colonizable with a biofilm in biotechnology process lines.

11. The method according to any one of claims 1 to 10, characterized in that one or a mixture of several QQ compounds is incorporated or applied onto or into a surface.

12. The method according to claim 1, characterized in that the surface colonizable with a biofilm is coated with a varnish, paint, or impregnate containing phenylethylamides, tryptamides, xenofuranones, xenocoumacins, prexenocoumacins, amicoumacins, preamicoumacins, and / or PAX peptides or mixtures of one or more of these components.A coating composition for treating surfaces to prevent the formation of biofilms, biofouling, or biocorrosion on a surface, comprising one or more quorum quenching (QQ) compounds selected from the group consisting of phenylethylamides, tryptamides, xenofuranones, xenocoumacins, prexenocoumacins, amicoumacins, preamicoumacins, and / or PAX peptides.

14. The coating composition according to claim 12, characterized in that it is a mixture of at least two of the quorum quenching (QQ) compounds.

15. The coating composition according to claim 12 or 13, characterized in that it is a mixture of phenylethylamides and tryptamides.

16. The coating composition according to claim 13, characterized in that the method according to claim 1, characterized in that the surface is treated with a mixture of at least two of the quorum quenching (QQ) compounds. 17.Coating composition according to claim 13, characterized in that it is a mixture of phenylethylamides and tryptamides.

18. The coating composition according to claim 13, characterized in that the phenylethylamides, tryptamides, xenofuranones, xenocoumacins, prexenocoumacins, amicoumacins, preamicoumacins, and / or PAX peptides originate from extracts of entomopathogenic bacteria of the genus Photorhabdus and Xenorhabdus.

19. The coating composition according to claim 13, characterized in that the xenocoumacin is xenocoumacin-1 or xenocoumacin-2.

20. The coating composition according to claim 13, characterized in that the composition is a varnish.

21. The coating composition according to claim 13, characterized in that the composition is a paint.

22. The coating composition according to claim 13, characterized in that the composition is an impregnate. 23.Use of one or more quorum quenching (QQ) compounds selected from the group consisting of phenylethylamides, tryptamides, xenofuranones, xenocoumacins, prexenocoumacins, amicoumacins, preamicoumacins, and / or PAX peptides to prevent the formation of biofilms, biofouling, or biocorrosion on surfaces.

24. Use according to claim 23, characterized in that it is a mixture of at least two of the quorum quenching (QQ) compounds.

25. Use according to claim 23 or 24, characterized in that it is a mixture of phenylethylamides and tryptamides.

26. Use according to claim 23, characterized in that the phenylethylamides, tryptamides, xenofuranones, xenocoumacins, prexenocoumacins, amicoumacins, preamicoumacins and / or PAX peptides are obtained from extracts of entomopathogenic bacteria of the genus Photorhabdus and Xenorhabdus. 27.Use according to claim 23, characterized in that the xenocoumacin is xenocoumacin-1 or xenocoumacin-2.

28. Use according to claim 23, characterized in that the surface is a surface colonizable with a biofilm in ships.

29. Use according to claim 23, characterized in that the surface is a surface colonizable with a biofilm in drinking water pipes.

30. Use according to claim 23, characterized in that the surface is a surface colonizable with a biofilm in process pipes.

31. Use according to claim 23, characterized in that the surface is a surface colonizable with a biofilm in process pipes in the food industry.

32. Use according to claim 23, characterized in that the surface is a surface colonizable with a biofilm in process pipes in biotechnology. 33.Use according to claim 23, characterized in that one or a mixture of several QQ compounds is incorporated or applied onto or into a surface.

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