DE102008009591A1 - Zwitterionic guanidinium compounds as selective antimicrobial agents - Google Patents

Abstract

The present invention relates to compounds corresponding to formula I and / or a physiological salt thereof and / or stereoisomeric forms thereof. May be: a) a hydrogen atom, b) (C 1 -C 3) -alkyl radical, R 6 may be: a) - (CH 2) n-COO- where n = 0-4, b) - (CH 2) n-SO3- where n = 0-4, c) an amino acid substituent such that the amino group of the amino acid forms part of a guanidinium derivative corresponding to formula I. The present invention further relates to compounds corresponding formula II and / or a physiological salt thereof and / or stereoisomeric forms thereof. May be: a) a hydrogen atom, b) (C 1 -C 3) -alkyl radical, R 5 may be: a) a hydrogen atom, b) (C 1 -C 3) -alkyl radical, c) - (CH 2) n- COO- with n = 0-4, d) - (CH 2) n -SO 3 - with n = 0-4, R 6 and R 7 can be independent of one another: a) a hydrogen atom, b) (C 1 -C 3) -alkyl radical, c ) a hydroxyl group, d) - (CH2) n-COO- where n = 0-4, ...

Description

The fight and prevention of infection and contamination by pathogenic and opportunistic pathogens from the enterobacteria group is an urgent task of medicine, but also of food processing Industry. The consumer expects from a food that it's the nutritional value, taste quality, Freshness and its natural Preserved texture. This requires new, innovative treatments, which allow the level of antimicrobial additives or the rigor of the treatment conditions without compromising food safety. traditional Methods of treatment of foods such. B. heating, drying, smoking, Corning, acidify and fermenting, which have been empirically used since time immemorial were developed into controlled industrial processes. Furthermore, the food preservation by cooling vacuum packaging and packaging under modified gas atmosphere improved. As consequence from the consumer's preference for "natural" foods intense salted or very sour foods not popular. The technical solution consists in the application of the so-called "hurdles" concept, i. H. in the introduction many gentle barriers to inhibiting microbial growth, instead of individual drastic measures (Leistner 1992; McMeekin 2007). Fermented foods are an example of such a series of "hurdles". A commonly used Safety often along with other measures, is the moderate reduction in water activity, eg. B. by addition of NaCl.

Some examples for widespread pathogenic bacteria associated with food could be, are the Gram-positive Clostridium botulinum, Bacillus cereus, Listeria monocytogenes and the Gram-negative Salmonella sp. and toxin-producing E. coli. Members of the Enterobacteriaceae family, z. As the genera Escherichia, Salmonella, Klebsiella, Yersina u. a., the food industry face big problems because they are species and include serotypes, who may be involved in food poisoning, the consequences of which are mild to serious Symptoms (eg kidney failure) to death. In particular Salmonella and Escherichiia spp., have often been infected with food and again and again, outbreaks are observed those of poultry, Meat, meat products, eggs and chocolate go out (Tauxe 1997).

research results prove that survival and persistence of pathogenic enterobacteria often with the ability correlate to biofilm formation and increased virulence. Some Toxin-producing E. coli are already in extremely low dosage infectious (<10 cells). Here are the early ones Stages of competition are crucial, and organisms in excess with higher Growth rate quickly becomes the dominant microflora. Provided at this critical stage "hurdles" are applied can, inhibit the pathogenic species of enterobacteria, their competition with Gram-positive Bacteria and other unaffected species diminish what to a favoritization of the desired and a repression the unwanted Microflora leads.

The Control of microbial contamination by physicochemical measures such as B. Reduction of water activity is often due to the presence Compatible solutes in the food and the ability of microbes, these as protective substances and survival aids to use complicated. It is known that compatible solutes used by microorganisms to adapt in a low water activity environment and growth under adverse environmental conditions (da Costa et al., 1998). In the majority of these compatible solutes These are substances with a zwitterionic structure, via recording systems for osmolytes accumulated, such. ProU / proP in E. coli and other enterobacteria or similar Transport systems such. B in B. subtilis, Corynebacterium glutamicum, Staphylococcus aureus, Listeria monocytogenes and others. The accumulation compatible solute by microorganisms can therefore be considered a more general, more flexible Mechanism of stress adaptation to be considered Food safety and hygiene counteracts. Preferred substances the zwitterions are glycine betaine and ectoine or derivatives thereof. About that It is also known that many recording systems are not very specific but transport a wide range of different substances (Peddie et al., 1998).

What applies to food safety, hygiene and control of microbial growth in food can be at least partially applied to personal hygiene and personal hygiene. The skin is populated as a relatively dry location of moderate salinity from a microflora composed to a large extent of osmotolerant microorganisms, some of which (e.g., Corynebacterium, Propionibacterium, Staphylococcus, Micrococcus species) develop from impure skin or even be involved in skin diseases (Woodroffe & Shaw 1974). As with the persistent, contaminating bacteria on fish and meat products, the use of compatible solutes as stress relievers by microorganisms also plays an important role in the skin location, especially in connection with infections and irritations of the skin Skin. Apart from that, a colonization of the skin surface with organisms from the group of enterobacteria i. R. undesirable and may, especially in the area of the oral cavity, the respiratory tract and the genitourinary tract also cause serious infections.

Genome sequence comparisons have led to the realization that, although most bacteria use the proton motive force for energy generation and transport processes, cyclic transport processes via Na ⁺ ions are also very common in bacteria. These include z. For example, primary sodium pumps (dicarboxylate decarboxylases, Na-transporting respiratory chains and sodium ATPases) and antiporters that convert a proton gradient into a sodium gradient and vice versa (NhaA-D, NhaP) (Hase et al., 2001). In addition, efflux pumps using sodium ion as the driving force and attributed to the multiantimicrobial extrusion family (MAIE) were discovered (Brown et al., 1999). Finally, the Na + -dependent motility of many pathogenic microorganisms has been recognized as an important virulence factor. Primary sodium pumps and Na ⁺ / H ⁺ antiporter are therefore new potential targets for antimicrobial agents that selectively attack only certain groups of microorganisms (and with minimal side effects), the so-called "smart drugs". One of the first inhibitors of this type is Korormycin, an antibiotic of a marine pseudoaltermonas species directed against the Na ⁺ transporting respiratory chain (NQR) of other marine bacteria. The diuretic agent amiloride, an important inhibitor of the Na ⁺ / H ⁺ antiporter of mammals, had no effect on the Nha-type antiporter of E.coli, but on the NhaB-type antiporter, but only on "inside-out" Vesicles (Pinner et al., 1995). 2-Aminoperimidine, on the other hand, inhibited the Nha-type antiporter of E. coli, but again only on inverted vesicles (Dibrov et al., 2005). Both compounds have a guanidinium group as a structural element. It is therefore believed that the guanidinium cation simulates a triply hydrated Na ⁺ ion and competes for binding sites. Since both substances in bacteria only act on inverted vesicles and not on living cells, it can be assumed that they either are not absorbed into the cells or are immediately re-exported by living cells.

It can therefore be stated that at the present time there are still no specific inhibitors which specifically attack the bacterial sodium transporters or their Na ⁺ / H ⁺ antiporter.

Surprisingly, it has now been found that the naturally occurring zwitterionic guanidinium compound creatine (C ₄ H ₉ N ₃ O ₂ ) is accumulated at reduced water activity in E. coli via the osmolyte transport systems proU and / or proP. Contrary to what is expected for compatible solutes, creatine does not have a positive influence on growth, but leads to a drastic reduction of the growth rate in the concentration range of 0.1-2 mM (Example 1, 1 ). This effect is enhanced with increasing salinity and temperature ( 2 and 3 ). Since creatine structurally resembles the well-known compatible glycine betaine, it is apparently "accidentally" accumulated as a solute in the cytoplasm, where it exerts its inhibitory influence. This surprising finding applies to a wide range of organisms with suitable recording system for compatible solutes of similar type, but especially for members of the family Enterobacteriaceae (eg Escherichia, Klebsiella, Salmonella, Yersinia, Serratia species and many others). Escherichia coli has been shown to enhance the antimicrobial effect with increasing salinity and increasing temperature ( 2 and 3 ), whereas many Gram-positive bacteria (eg Bacillus sp., Corynebacterium glutamicum, Staphylococcus carnosus) remained unaffected. By investigating mutants deleted from individual components of the sodium cycle, a specific effect on this target could be demonstrated. Using compounds of the formula I and II, it is therefore possible for the first time to actively introduce a zwitterionic guanidinium compound into living cells and to selectively inhibit components of the Na ⁺ cycle there.

The present invention claims the use of compounds according to formula I and II which are characterized in that they have a) a zwitterionic structure and are readily soluble in water and b) under physicochemical conditions as described, for example, in US Pat. B. present in food and are used in the food industry (eg., Reduced water activity and / or low pH and / or high pressure) or in everyday life in the field of hygiene and personal care or in pathological situations experienced by pathogenic Microbes, preferably from the group of enterobacteria, are taken up and accumulated as putative protective substances and specifically inhibit the Na ⁺ cycle there. Among the spectrum of claimed compounds for the field of food safety, hygiene and skin care are preferably the naturally occurring creatine (Wyss & Kaddurah-Daouk, 2000) as well as positional and structural isomers of these compounds, in connection with the treatment of irritations and diseases thereof In addition, the non-naturally occurring 1,4,5,6-tetrahydro-2-amino-4-pyrimidincarboxylsäure and their hydroxy derivatives. The compounds should preferably be ectopic by spraying, washing or dipping in solution or as a component shear formulations are applied. The aim is to selectively inhibit microbial growth of pathogens from the group of enterobacteria, to increase positive effects and / or to reduce side effects.

Formel I

Formula I

• a) ein Wasserstoffatom
• b) (C1-C3)-Alkylrest

R1-R5 can be:

• a) a hydrogen atom
• b) (C 1 -C 3) -alkyl radical

• a) -(CH₂)_n-COO^– mit n = 0–4
• b) -(CH₂)_n-SO₃ ^– mit n = 0–4
• c) ein Aminosäuresubstituent, dergestalt dass daraus eine Verbindung entsteht, in der die Aminogruppe der Aminosäure Teil eines Guanidinium-Derivats entsprechend Formel I bildet

Formel II R6 can be:

• a) - (CH ₂ ) _n -COO ^- where n = 0-4
• b) - (CH ₂ ) _n -SO ₃ ^- where n = 0-4
• c) an amino acid substituent, such that it forms a compound in which the amino group of the amino acid forms part of a guanidinium derivative corresponding to formula I.

Formula II

• a) ein Wasserstoffatom
• b) (C1-C3)-Alkylrest

R1-R4 can be:

• a) a hydrogen atom
• b) (C 1 -C 3) -alkyl radical

• a) ein Wasserstoffatom
• b) (C1-C3)-Alkylrest
• c) -(CH₂)-COO^– mit n = 0–4
• d) -(CH₂)_n-SO₃ ^– mit n = 0–4

R5 can be:

• a) a hydrogen atom
• b) (C 1 -C 3) -alkyl radical
• c) - (CH ₂ ) -COO ^- where n = 0-4
• d) - (CH ₂ ) _n -SO ₃ ^- where n = 0-4

• a) ein Wasserstoffatom
• b) (C1-C3)-Alkylrest
• c) eine Hydroxylgruppe
• d) -(CH₂)_n-COO^– mit n = 0–4
• e) -(CH₂)_n-SO₃ ^– mit n = 0–4

x kann 1, 2 oder 3 sein.R6 and R7 can be independent of each other:

• a) a hydrogen atom
• b) (C 1 -C 3) -alkyl radical
• c) a hydroxyl group
• d) - (CH ₂ ) _n -COO ^- where n = 0-4
• e) - (CH ₂ ) _n -SO ₃ ^- where n = 0-4

x can be 1, 2 or 3.

Examples for the Application in the food sector, for personal hygiene, personal care and cosmetic formulations, as well as for medicine and pharmacy listed below:

1. Control of pathogenic enterobacteria in food and the food processing industry

a) Hygiene in the food sector

The Contamination of foods with enterobacteria may already be done on the farm (or on the trawler) and cross the chain continue the processing and sales processes. Examples on Beginning of the chain are z. B. cattle and sheep skins, the contamination of eggs in the ovaries of chickens, contaminated seeds and manually treated fish and meat products. In the further processing process, contact surfaces, sewers, Connecting elements and much more as a source of enterobacteria found. In many cases Establishes an enterobacteria flora permanently in food factories, because persistent strains in protected Survive niches, often in biofilms that allow attachment to surfaces as a source of nutrients serve and protect against chemical and physical treatment (Holah et al. 2004).

The The present invention seeks to target enterobacteria in the area food production, processing and handling (i.a. also in biofilms). Due to the zwitterionic nature and the good water solubility the substances according to the invention Biofilms are permeated and the antimicrobial compounds are active taken up in the cells.

b) Conventional treatment of carcasses

Of the Process of meat production in cattle includes the skinning and the removal of the intestines after slaughter. For both processes can the carcass be contaminated with enterobacteria (Gill 2005). At this time lies the temperature of the carcasses on the surface yet close to that of the living animal and can after the o. g. processing still over 30 ° C, when the carcasses be transferred to the cold rooms.

The present invention aims to target primarily enterobacteria and other acceptable Pa combat thogens. The main factor on the growth rate is the temperature. In particular, in the case of elevated temperatures, the invention will be useful because under these conditions, pathogens (in the absence of further obstacles) become increasingly competitive, while at the same time the effect of the antimicrobial substances with increased temperature increases. Naturally, the same applies to pork, poultry and other slaughter animals.

c) The removal of bone in the warm Status

This Process provides an alternative to the conventional processing process and means that the bones are in the warm state before entering of rigor mortis and before vacuum packaging. That has economic Benefits for the manufacturer, but means additional manipulation and contamination risk, even if it's big and whole as the conventional method in hygienic terms equivalent is classified.

The The present invention provides a methodology which is described in U.S. Pat Location is E.coli and other enterobacteria in the early stages of cooling to inhibit when the temperature is still above 30 ° C and the growth of these Organism group is done very quickly.

d) Fermented foods

The Fermentation of meat, fish and other foods a mixed bacterial flora, and especially lactic acid bacteria, is a traditional process that evolves empirically and is based on promoting the multiplication of the desired microbial flora. In modern fermentation practice became the classical method displaced by the targeted use of starter cultures (Adams & Moss 2006). there can also other than lactic acid bacteria be used (for example, Staphylococcus carnosus) to certain product properties (Smell and taste). Gram-negative enterobacteria (eg, E. coli and Salmonella), although initially present, are not he wishes and i will. R. displaced with time. This process can be through Application of the present invention actively supported and be accelerated. It is important to mention that the substances according to the invention the development of Gram positive microorganisms and desirable the associated properties of the product are not affected.

e) Other applications related with food and food processing processes

There the present invention for the food sector pursues the goal of growing susceptible pathogenic microorganisms, essentially from the group of enterobacteria, too inhibit and concomitantly other organisms, mainly from To promote the group of Gram-positive bacteria, the range of possible ones goes Applications over the o. g. Examples beyond. The invention can also be applied to others Process of food preservation and food safety are used, such. B. drying, smoking, pickling and high pressure treatment (HPP) in which the growth of enterobacteria is at an early stage must be controlled.

2. Personal hygiene and body care

in the home Environment and in the field of personal Hygiene and body care can the substances according to the invention also be used. Products based on compounds of the formula I and II can be designed to increase the effectiveness of existing ones Reinforce household cleaning and disinfecting solutions or independent, represent new products.

The Human skin is an organ that needs proper care. The air-exposed areas are usually "dry" and populated by a bacterial flora, which is dominated by Gram-positive organisms (Woodroffe & Shaw 1974). Other Areas such. B. armpits and toe spaces are "wet" zones in which the Colonization with Gram-negative bacteria is favored. Examples of the application in skin care are cleaning solutions for the skin, skincare creams, Moisturizers and formulations for the treatment of infections and irritations of the skin (eg Sunburn). The danger of infection with potential pathogens exists also in the area of the oral cavity and the gums (z. B. Porphyromonas gingivalis), as well as for the urogenital area the known opportunistic pathogens from the group of enterobacteria. The present invention can be used to specifically attack enterobacteria and other potentially pathogens, which colonize these zones. something similar applies to Areas that due to bandages etc. a moist microclimate to generate.

3. Selective antimicrobial Active ingredients for Medicine and pharmacy

Possibly due to high Na ⁺ concentrations in blood and other body fluids ha Many human and animal pathogenic microorganisms have Na ⁺ -dependent transport systems for amino acids and accordingly also primary sodium pumps and Na ⁺ / H ⁺ antiporters. Examples of such Na ⁺ -dependent pathogenic genera are:
Treponema, Chlamydia, Porphyromonas, Neisseria, Pasteurella, Haemophilus, Vibrio, Pseudomonas, Escherichia, Salmonella, Klebsiella and Yersinia.

Since the substances according to the invention corresponding to formulas I and II are accumulated by these organisms and interfere there with components of the Na ⁺ cycle (eg NQR and / or antiporter), a targeted use against these pathogens is possible by exploiting a completely new target , Even if only a very limited range of organisms were achieved by the use of these antimicrobial substances, they could nevertheless be a very effective supplement to existing therapy concepts, especially in the case of persistent infections.

From the compounds according to formula For this reason, creatine is also the preferred compound for the food industry. because it's a natural one Component higher Is living thing. It is used in vertebrates as energy storage (in form of creatine phosphate) and is high in meat and fish (2-10 g / kg). Creatine is internationally recognized as a valuable nutritional supplement for athletes and Vegetarian recognized and as a food additive and for the topical Application harmless. Of the compounds of formula II 1,4,5,6-tetrahydro-2-amino-4-pyrimidinecarboxylic acid or its 5-hydroxy variant for the Especially medical and pharmaceutical applications preferred because they are derivatives of naturally occurring compatible Solute L-ectoine and S, S-β-hydroxyectoine, which are recognized by numerous transport systems for compatible solute and be accumulated.

Example 1:

Effect of creatine on the growth rate of E. coli K12 depending of salinity and temperature

E. coli K12 was cultured to determine the growth rates in glucose-mineral salt medium MM63 (modified according to Larsen et al., 1987) in the absence and in the presence of creatine at different salinities and at different temperatures. The antimicrobial effect is particularly pronounced in the concentration range of 0.1 to 2 mM. It correlates with the salinity of the medium and is increased disproportionately by increasing the temperature ( 1 . 2 and 3 ).

The present invention further claims the use of derivatized amino acids according to formula I or cyclic variants according to formula II as selective antimicrobial substances, which are characterized in that the α- and / or another amino group of an amino acid in a simple process to a guanidinium derivative is modified. Such guanidinium derivatives are obtained by reacting the amino group (s), if appropriate in modified form, with equimolar amounts of O-methylisourea at elevated pH and purifying them in a simple process (Example 2, 4 ). For the preparation of the cyclic variants, the procedure according to known methods by z. B. bifunctional diamino acids and reagents of the type NH = C (R1, R2) are reacted, wherein R1 and R2 good leaving groups such. B. represent -O-CH ₃ .

Example 2:

Synthesis of N-amidino-alanines, a Structural isomers of creatine

To an aqueous solution of alanine (1 M) is added an equimolar amount of O-methyl isourea. The pH is adjusted to pH 10 with Ca (OH) ₂ and the solution is heated to 50 ° C. for at least 2 hours. It is then neutralized with sulfuric acid and the precipitated CaSO ₄ separated by filtration and / or centrifugation. The solvent water is removed by rotary evaporation (at reduced pressure) or by lyophilization. The purity of the crude product or the crystallized product is checked by HPLC or NMR ( 4 ). Yield of N-amidino-alanines: at least 80% (crude product).

Literature:

• Adams MR and Moss MO (2006) The Microbiology of Food Preservation in Food Microbiology, 2nd Edition, Royal Society of Chemistry, London ,
• Brown MH, Paulsen IT, Skurray RA (1999) The multidruc efflux protein NorM is a prototype of a new family of transporters. Mol Microbiol 31: 394-395
• da Costa MS, Santos H, Galinski EA (1998) An overview of the role and diversity of compatible solutes in Bacteria and Archaea. Adv Biochem Eng Biotechnol 61: 117-153
• Dibrov P, Rimon A, Dzioba J, Winogrodski A, Shalitin Y, Padan E (2005) 2-Aminoperimidines, a specific inhibitor of bacterial NhaA Na + / H + antiporter. FERS Lett 579: 373-378
• Gill CO (2005) Sources of microbial contamination at slaughtering plants, pp. 231-243 in Improving the Safety of Fresh Meat, JN Sofos (Editor), CRC Boca Raton and Woodhead Publishing, Cambridge ,
• Cheese CC, Fedorova ND, Galperine MY, Dibrov PA (2001) Sodium ion cycle in bacterial pathogens: evi dence from cross-genome comparison. Microbiol Mol Biol Rev 65: 353-370
• Holah JT, Bird J and Hall KE (2004) The microbial ecology of high risk, chilled food factories; evidence for persistent Listeria spp. and Escherichia coli strains. Journal of Applied Microbiology 97: 68-77 ,
• Larsen PI, Sydnes LK, Landfald B, Electricity AR (1987) Osmoregulation in Escherichia coli by accumulation of organic osmolytes: betaines, glutamic acid and trehalose. Arch Microbiol 147: 1-7
• Leistner L. (1992). Food preservation by combined methods. Food Research International 25: 151-158 ,
• McMeekin TA (2007) Predictive microbiology: quantitative science delivering quantifiable benefits to the meat industry and other food industries. Meat Science 77: 17-27 ,
• Peddie BA, Wong-She J, Randall K, Lever M, Chambers ST (1998) Osmoprotective properties and accumulation of betaine analogues by Staphylococcus aureus. FEMS Microbiol Lett 160: 25-30
• Pinner E, Padan E, Schuldinger S (1995) Amiloride and Harmalins are potent inhibitors of NhaB, a Na + / H + antiporter from Escherichia coli. FERS Lett. 365: 18-22
• Tauxe RV (1997) Emerging Food Borne Diseases: an evolving public health challenge. Emerging Infectious Diseases 3: 425-433 ,
• Woodroffe RCS and Shaw DA. (1974). Natural control and ecology of microbial populations on skin and hair, pp. 13-34 in The Normal Microbial Flora of Man, FA Skinner and JG Carr (editors), Society for Applied Bacteriology, Symposium Series no. 3, Academic Press, London ,
• Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiological Reviews 80: 1107-1213

Claims (21)

Compounds corresponding to formula I and / or a physiological salt thereof and / or stereoisomeric forms thereof, characterized in that they have zwitterionic structure and the radicals are defined as follows:

Formula I R 1 -R 5 can be: a) a hydrogen atom b) (C 1 -C 3) -alkyl radical R 6 can be: a) - (CH ₂ ) _n -COO ^- where n = 0-4 b) - (CH ₂ ) _n -SO ₃ ^- with n = 0-4 c) an amino acid substituent, such that the amino group of the amino acid forms part of a guanidinium derivative corresponding to formula I. Compounds corresponding to formula II and / or a physiological salt thereof and / or stereoisomeric forms thereof, characterized in that they have zwitterionic structure and the radicals are defined as follows:

Formula II R 1 -R 4 can be: a) a hydrogen atom b) (C 1 -C 3) -alkyl radical R 5 can be: a) a hydrogen atom b) (C 1 -C 3) -alkyl radical c) - (CH ₂ ) _n -COO ^- with n = 0-4 d) - (CH ₂ ) _n -SO ₃ ^- where n = 0-4 R 6 and R 7 can be independently of one another: a) a hydrogen atom b) (C 1 -C 3) -alkyl radical c) a hydroxyl group d) - (CH ₂ ) _n -COO ^- where n = 0-4 e) - (CH ₂ ) _n -SO ₃ ^- where n = 0-4 x can be 1, 2 or 3. A compound of the formula C ₄ H ₉ N ₃ O ₂ (MU 130), creatine or a structural isomer of creatine, characterized in that a positively charged guanidinium structural element is combined with a negatively charged carboxyl group (zwitterion), corresponding to formula I. A compound of the formula C ₅ H ₉ N ₃ O ₂ (MW 143) or C ₅ H ₉ N ₃ O ₃ (MW 159), a guanidinium derivative of the natural compatible solute ectoine and S, S-β-hydroxyectoine, characterized in that a cyclic guanidinium structural element is combined with a negatively charged carboxyl group (zwitterion), corresponding to formula II A procedure for the derivatization of amino acids (including diamino acids), the N-amidino derivatives of the amino acids according to claim 1 or cyclic structures according to claim 2 produced, characterized in that the amino acids in a simple process with O-methyl isourea or with reagents of the type NH = C (R1, R2) are reacted to form said zwitterionic Guanidinium derivatives to produce, with the preferred amino acids following are: the 20 proteinogenic amino acids and β-alanines, γ-aminobutyrate, Nε-acetyllysine, Nα-acetyllysine, Nδ-acetylornithine, Nα-acetylornithine, N r-Acetyldiaminobutyrat, Nα-Acetyldiaminobutyrat, 2,4-diaminobutyrate, 2,3-diaminopropionate, 2,5-diaminovalerate and additionally also their N-methyl derivatives (eg sarcosine), as well as all mentioned amino acids as S and R stereoisomers. Use of at least one of the compounds according to claim 1-4 as selective antimicrobial agent in the food sector, for personal hygiene, personal hygiene and cosmetics as well as for Medicine and pharmacy. Use of natural creatine (C ₄ H ₉ N ₃ O ₂ , MG 130), both alone and in combination with at least one of the compounds according to claims 1-4 as a selective antimicrobial agent in the food industry, for personal hygiene, personal care and cosmetics and for Medicine and pharmacy. Use of a cyclic guanidinium derivative of the naturally occurring compatible solutes Ectoin and S, S-β-hydroxyectoine (C ₅ H ₉ N ₃ O ₂ , MG 143 or C ₅ H ₉ N ₃ O ₃ , MW 159), both alone also in combination with at least one of the compounds according to claim 1-4 as a selective antimicrobial agent in the food industry, for personal hygiene, personal care and cosmetics as well as for medicine and pharmacy. The composition of an aqueous solution or a mixture of Water and alcohol are characterized in that they contain creatine and / or at least one of the compounds according to claims 1-4 in one Concentration of 1 μM to 100 mM. The composition of a solution according to claim 9, characterized that they also contain physiological salts (eg NaCl) in one concentration of 0.001 and 5%. The composition of a solution according to claim 9 and / or 10, characterized that they additionally also contains other antimicrobial substances. The composition of a cosmetic formulation, or a lotion for Skin and body care for the treatment of infections and irritations of the skin, thereby in that it contains creatine and / or at least one of the compounds according to claim 1-4 in a concentration of 0.1-5% contains. The composition of a cosmetic formulation or a lotion for Skin and body care according to claim 12, characterized in that it also physiological salts (z. B. NaCl) in a concentration of 0.001 to 5%. The composition of a cosmetic formulation or a lotion for Skin and body care according to claim 12 and / or 13, characterized in that they additionally also contains other cosmetic ingredients. A method to combat / prevent microbial Contamination, to improve food safety and to Process optimization in the food sector, characterized that natural Creatine and / or at least one of the compounds according to claim 1-4 and / or at least one of the solutions according to claim 9-11 used becomes. A method to combat / prevent microbial Contamination, to improve food safety and to Process optimization in the food sector according to claim 15, characterized in that that in addition also reduced water activity and / or low pH and / or other physicochemical methods (eg, high pressure). A method for controlling / avoiding microbial contamination, for improving food safety and for process optimization in the food sector according to claim 15 and / or 16, characterized in that the substances or the solutions are directly applied, sprayed or otherwise (eg. Immersion, washing, etc.) are brought into contact with the foodstuffs, preferably to such an extent that the applied amount of the compounds according to claims 1-4 in solution in a range of 0.01-10 mM or on surfaces in a range of 0.5 μg to 0.5 mg / cm ² . A method of personal hygiene and body care or for the treatment of irritations and infections of the skin, thereby characterized that, natural Creatine and / or at least one of the compounds according to claim 1-4 and / or at least one of the cosmetic formulations according to claim 12-14 is used. A method of personal hygiene and body care or for the treatment of skin irritation and infection as claimed 18, characterized in that the use in combination with and / or for support other treatments. A method of personal hygiene and body care or for the treatment of irritation and infection of the skin according to claim 18 and / or 19, characterized in that the substances or cosmetic formulations directly applied, sprayed or otherwise (eg , Rubbing, application, etc.) is applied to the surface of the skin, preferably to the extent that the applied amount of the compounds according to claims 1-4 is in a range of 0.5 μg to 0.5 mg / cm ² . Medicinal application for the targeted treatment of irritations and infections caused by susceptible bacteria, preferably enterobacteria, characterized in that substances according to any one of claims 1-4 are administered via standard methods of antimicrobial therapy, preferably components of the microbial Na ⁺ Cycle are inhibited.