PL246720B1 - Antimicrobial lipopeptides, a pharmaceutical composition and a cosmetic composition containing them and applications - Google Patents

Abstract

The present invention relates to synthetic antibacterial lipopeptides having a linear structure and antibacterial lipopeptides having a branched structure, pharmaceutical compositions containing such lipopeptides, cosmetic compositions containing such lipopeptides, and lipopeptides for use as a medicament, and lipopeptides for use in the treatment or prophylaxis of a bacterial infection.

Description

Description of the invention

The present invention relates to new synthetic, linear and branched lipopeptides, pharmaceutical compositions containing such synthetic, linear and/or branched lipopeptides and cosmetic compositions containing such synthetic, linear and/or branched lipopeptides, as well as to such linear and branched lipopeptides for use as medicaments, especially in the treatment of bacterial infections.

The increasing number of drug-resistant bacterial strains is currently a serious clinical problem. Therefore, there is a need for new compounds that could be an effective alternative to existing antibiotics. At the same time, it is desirable that they exhibit different mechanisms of action compared to traditional antibiotics. A group of chemical compounds that can meet these requirements are lipopeptides.

Traditional antibiotics available on the market usually have specific effects and can, for example, disrupt specific biochemical processes by affecting the activity of enzymes involved in cell wall synthesis or by damaging DNA. Lipopeptides have a different mechanism of action, using their ability to penetrate and irreversibly destroy the structure of the bacterial cell membrane (see, for example, Alborn et al., Antimicrob. Agents Chemother. 35 (1991) 2282). This fact has important implications for their use as antibacterial agents, because the probability of resistance to such compounds is very low.

Lipopeptides include daptomycin, which is a natural, branched, cyclic antibiotic lipopeptide of nonribosomal origin. This lipopeptide has a strong bactericidal effect in vitro and in vivo against gram-positive bacteria that can cause serious and life-threatening diseases, as described, for example, in the publication by Taiły et al. (Taiły, F.P. et al., "Daptomycin: a Novel Agent for Gram positive Infections", Exp. Opin. Invest. Drugs 8 (1999) 1223-1238).

The group of lipopeptides that show significant potential as useful antibiotics include those described, for example, in U.S. Patent No. 6,911,525 and U.S. Patent Application No. 2015/0080292 A1.

J. Juhaniewicz-Dębińska et al. (Juhaniewicz-Dębińska et al., "Lipopeptide-induced changes in permeability of solid supported bilayers composed of bacterial membranę lipids", Journal of Electroanalytical Chemistry, 812, (2018) 227-234) described ultrashort linear lipopeptides and their effect on simplified models of lipid bilayers mimicking the membrane system of the gram-negative bacterium E. coli. Studies have shown significant membranolytic activity of the mentioned lipopeptides, which suggests that their mechanism of antibacterial action may indeed be based on interaction with the cell membrane.

Most of the lipopeptides described in the literature are of natural origin and are obtained from bacteria or other organisms, which entails the costs of isolation from biological material. Moreover, most of the lipopeptides currently used in medicine, such as daptomycin or polymyxins, have a cyclic, relatively complex structure, which in turn complicates the potential synthesis and further modifications.

The aim of the present invention is to provide synthetic lipopeptides that exhibit antibacterial activity against Gram-positive and Gram-negative bacteria, including antibiotic-resistant bacteria, as well as pharmaceutical and cosmetic compositions containing them.

Brief description of the invention

The subject of the invention is a synthetic lipopeptide of the general formula:

Xi-Dab-X2-X ₃ -Dab-Dab-X4-NH ₂ in which

Xi is a residue selected from FA-DDab-Dab (SEQ ID NO: 1) and H-Dab(FA-DDab) (SEQ ID NO: 3), wherein when Xi is FA-DDab-Dab then FA is a fatty acid residue selected from the group consisting of n-dodecanoic acid, n-decanoic acid and 4-methylnonanoic acid, and when Xi is H-Dab(FA-DDab) then FA is a fatty acid residue selected from the group consisting of n-dodecanoic acid, n-decanoic acid and 4-methylnonanoic acid;

Χ2 denotes a leucine, alanine, isoleucine or valine residue;

Χ3 is a D-phenylalanine, D-tyrosine or D-tryptophan residue; and

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X4 represents a leucine, alanine, isoleucine or valine residue.

Preferably, in the lipopeptide of the above-mentioned general formula according to the invention, Xi denotes FA-DDab-Dab, Χ2 denotes a leucine residue, Χ3 denotes a D-phenylalanine residue, and Χ4 denotes a leucine residue. Such a lipopeptide has a linear structure and can be represented by the following formula:

FA-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (SEQ ID NO: 2).

More preferably, such a lipopeptide according to the invention is selected from the group consisting of the following lipopeptides:

CHiiCHijęCHiCO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NHii(abbreviated formula 1), CH ₃ (CHi)7CH2CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH2(abbreviated formula 2), and CH ₃ (CH2)5CH2CH(CH ₃ )CH2CHiCO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH2 (abbreviated formula 3).

Preferably, in such a lipopeptide of the above-indicated general formula according to the invention, Χ1 denotes H-Dab(FA-DDab), Χ2 denotes a leucine residue, Χ3 denotes a D-phenylalanine residue, and Χ4 denotes a leucine residue. Such a lipopeptide has a branched structure and can be represented by the following formula:

H-Dab(FA-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH2(SEQ ID NO: 4).

Preferably, such a lipopeptide according to the invention is selected from the group consisting of: H-Dab( _CH3 (CH2)9CH2CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH2 (abbreviated formula 4), H-Dab( _CH3 (CH2)7CH2CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH2 (abbreviated formula 5), and H-Dab( _CH3 (CH2) _3CH2CH ( _CH3 )CH2CHiCO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH2 (abbreviated formula 6).

The subject of the invention is also a pharmaceutical composition characterized in that it contains a lipopeptide of the general formula:

Xi-Dab-X2-X ₃ -Dab-Dab-X ₄ -NH ₂ in which

Χ1 denotes a residue selected from FA-DDab-Dab and H-Dab(FA-DDab), wherein when Χ1 denotes FA-DDab-Dab then FA denotes a residue of a fatty acid selected from the group consisting of n-dodecanoic acid, n-decanoic acid and 4-methylnonanoic acid, when Χ1 denotes H-Dab(FA-DDab) then FA denotes a residue of a fatty acid selected from the group consisting of n-dodecanoic acid, n-decanoic acid and 4-methylnonanoic acid;

Χ2 denotes a leucine, alanine, isoleucine or valine residue;

Χ3 denotes a D-phenylalanine, D-tyrosine or D-tryptophan residue

Χ4 denotes a leucine, alanine, isoleucine or valine residue.

Preferably, the pharmaceutical composition according to the invention comprises a lipopeptide of the above-mentioned general formula according to the invention, wherein Χ1 denotes FA-DDab-Dab, Χ2 denotes a leucine residue, Χ3 denotes a D-phenylalanine residue and Χ4 denotes a leucine residue.

More preferably, the pharmaceutical composition of the invention comprises a lipopeptide selected from the group consisting of:

CH ₃ (CH2)?CHiCO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH2 (abbreviated formula 1), CH^CHiJ/CHzCO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NFhi (abbreviated formula 2), and CH ₃ (CH2) ₃ CHiCH(CH ₃ )CH2CH2CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH2 (abbreviated formula 3).

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Preferably, the pharmaceutical composition according to the invention comprises a lipopeptide of the above-mentioned general formula according to the invention, wherein Xi denotes H-Dab(FA-DDab), Χ2 denotes a leucine residue, Χ3 denotes a D-phenylalanine residue and Χ4 denotes a leucine residue.

More preferably, the pharmaceutical composition of the invention comprises a lipopeptide selected from the group consisting of:

H-Dab(CH ₃ (CH ₂ )9CHiCO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH2 (shortened formula 4),

H-Dab(CH ₃ (CH ₂ )7CH _and CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₁ (shortened formula 5), and

H-Dab(CH ₃ (CH2) ₃ CH2CH(CH3)CH2CH2CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH2 (shortened formula 6).

The pharmaceutical composition according to the invention preferably contains from 0.1 to 99% by weight of at least one of the above-described lipopeptides of the invention.

Preferably, the pharmaceutical composition according to the invention further comprises a pharmaceutically acceptable carrier and/or a diluent and/or an adjuvant and/or an excipient.

More preferably, the pharmaceutical composition according to the invention comprises corn starch and/or gelatin and/or lactose and/or sucrose and/or microcrystalline cellulose and/or kaolin and/or mannitol and/or dicalcium phosphate and/or sodium chloride and/or alginic acid.

Preferably, the pharmaceutical composition according to the invention is in a form suitable for oral and/or intravenous and/or intramuscular and/or subcutaneous and/or parenteral administration.

Preferably, the pharmaceutical composition according to the invention is in the form of a tablet and/or a capsule and/or an elixir and/or a suspension and/or a syrup and/or a gel and/or a cream and/or an ointment.

The subject of the invention is also a cosmetic composition characterized in that it contains a lipopeptide of the general formula:

Xi-Dab-X2-X ₃ -Dab-Dab-X ₄ -NH2 in which

Χ1 is selected from FA-DDab-Dab and H-Dab(FA-DDab), wherein when Χ1 is FA-DDab-Dab then FA is a fatty acid residue selected from the group consisting of n-dodecanoic acid, n-decanoic acid and 4-methylnonanoic acid, when Χ1 is H-Dab(FA-DDab) then FA is a fatty acid residue selected from the group consisting of n-dodecanoic acid, n-decanoic acid, 4-methylnonanoic acid and 4-methylhexanoic acid; Χ2 is a leucine, alanine, isoleucine or valine residue;

Χ3 denotes a D-phenylalanine, D-tyrosine or D-tryptophan residue

Χ4 denotes a leucine, alanine, isoleucine or valine residue.

Preferably, the cosmetic composition according to the invention comprises a lipopeptide of the above-mentioned general formula according to the invention, wherein Χ1 denotes FA-DDab-Dab, Χ2 denotes a leucine residue, Χ3 denotes a D-phenylalanine residue and Χ4 denotes a leucine residue.

More preferably, the cosmetic composition of the invention comprises a lipopeptide selected from the group consisting of:

CH ₃ (CH2)?CH2CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (short formula 1),

CH ₃ (CH 2 )7CH ₂ CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (shortened formula 2), and

CH ₃ (CH2) ₃ CH2CH(CH ₃ )CH2CH2CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH2 (shortened formula 3).

Preferably, the cosmetic composition according to the invention comprises a lipopeptide of the general formula indicated above, wherein Χ1 denotes H-Dab(FA-DDab), Χ2 denotes a leucine residue, Χ3 denotes a D-phenylalanine residue and Χ4 denotes a leucine residue.

More preferably, the cosmetic composition of the invention comprises a lipopeptide selected from the group consisting of:

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H-Dab(CH ₃ (CH ₂ ) ₉ CH ₂ CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (abbreviated formula 4), H-Dab(CH 3 (CH ₂ ) 7CH ₂ CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (abbreviated formula 5),

H-Dab(CH3( _CH2 ) _3CH2CH ( _CH3 )CH2CH2CO-DDab)-Dab-Leu _- DPhe-Dab-Dab-Leu- _NH2 (abbreviated formula 6) _{, and} H-Dab( _CH3CH2CH (CH3 _{) CH2CH2CO} -DDab)-Dab-Leu-DPhe-Dab-Dab-Leu- _NH2 (abbreviated formula 7).

Preferably, the cosmetic composition according to the invention contains from 0.1 to 99% by weight of at least one of the lipopeptides according to the invention.

Preferably, the cosmetic composition of the invention comprises a cosmetic carrier.

Preferably, the cosmetic composition according to the invention is in the form of a gel or cream or suspension. The invention further relates to any of the lipopeptides according to the invention as defined above for use as a medicament.

The invention further provides any of the lipopeptides of the invention as defined above for use in the treatment or prophylaxis of a bacterial infection.

Preferably, in the case of any lipopeptide of the invention for use in the treatment or prophylaxis of a bacterial infection, such bacterial infection is caused by a gram-positive bacterium.

More preferably, the bacterial infection is caused by a bacterium of the genus Enterococcus or Staphylococcus.

Even more preferably, the bacterial infection is caused by Staphylococcus aureus or Staphylococcus epidermidis.

Preferably, in the case of any lipopeptide of the invention for use in the treatment or prophylaxis of a bacterial infection, such bacterial infection is caused by a gram-negative bacterium.

More preferably, the bacterial infection is caused by a bacterium of the genus Klebsiella or Pseudomonas. Even more preferably, the bacterial infection is caused by Klebsiella pneumoniae or Pseudomonas aeruginosa.

Preferably, in the case of any lipopeptide of the invention for use in the treatment or prevention of a bacterial infection, such infection is caused by an antibiotic-resistant bacterium.

Preferably, in the case of the lipopeptide according to the invention for use in the treatment or prophylaxis of a bacterial infection, at _{least one lipopeptide selected from the group consisting of: CH3(CH2)9CH2CO - DDab} -Dab-Dab-Leu-DPhe-Dab-Dab-Leu- _NH2 (abbreviated formula 1), _CH3 ( _CH2 ) _7CH2CO -DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu- _NH2 (abbreviated formula 2),

CH ₃ (CK ₂ )3CH ₂ CH(CH ₃ )CH ₂ CH ₂ CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (abbreviated formula 3), H-Dab(CH 3 (CH ₂ ) ₉ CH 2 CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (abbreviated formula 4), H-Dab(CH ₃ (CH ₂ ) 7CH ₂ CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (abbreviated formula 5), and H-Dab(CH ₃ (CH ₂ ) ₃ CH ₂ CH(CH3)CH ₂ CH ₂ CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (abbreviated formula shortened 6).

Detailed description of the invention

As defined above, the present invention provides novel, synthetic, linear and branched lipopeptides, pharmaceutical compositions containing such synthetic, linear and/or branched lipopeptides, cosmetic compositions containing such synthetic, linear and/or branched lipopeptides, as well as such linear and branched lipopeptides for use as medicaments, especially in the treatment of bacterial infections.

The synthetic lipopeptide of the invention is represented by the general formula:

X ₁ -Dab-X ₂ -X3-Dab-Dab-X ₄ -NH ₂

PL 246720 Β1 in which

Xi is a residue selected from FA-DDab-Dab (SEQ ID NO: 1) and H-Dab(FA-DDab) (SEQ ID NO: 3), wherein when Xi is FA-DDab-Dab then FA is a fatty acid residue selected from the group consisting of n-dodecanoic acid, n-decanoic acid and 4-methylnonanoic acid, and the lipopeptide has a linear structure, and when Xi is H-Dab(FA-DDab) then FA is a fatty acid residue selected from the group consisting of n-dodecanoic acid, n-decanoic acid, 4-methylnonanoic acid and 4-methylhexanoic acid, and the lipopeptide has a branched structure;

Χ2 denotes a leucine, alanine, isoleucine or valine residue - i.e. an aliphatic amino acid;

Χ3 denotes a D-phenylalanine, D-tyrosine or D-tryptophan residue - i.e. an aromatic amino acid residue; and

Χ4 denotes a leucine, alanine, isoleucine or valine residue.

For purposes of this specification, a lipopeptide is a molecule consisting of a lipid moiety, i.e., a fatty acid (FA) moiety linked to a peptide moiety. Standard three-letter abbreviation nomenclature known in the art is used for amino acid residues, for example, the amino acid residue L-phenylalanine is designated as "Phe", the residue D-phenylalanine as "DPhe", the residue L-leucine as "Leu", the acid L-2,4-diaminobutyric acid as "Dab", and the acid D-2,4-diaminobutyric acid as "DDab". The sequence listing provides the amino acid sequences of the peptide portion of the lipopeptides of the invention.

Preferred linear lipopeptides of the present invention can be represented by the following formula:

FA-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (SEQ ID NO: 2) wherein FA is a linear or branched fatty acid residue selected from the group consisting of n-dodecanoic acid, n-decanoic acid and 4-methylnonanoic acid. The detailed structures of the more preferred linear lipopeptides of the invention are shown in Table 1.

Table 1. Linear lipopeptides

No. Model Lipopeptide short formula Structural formula 1 CH ₃ (CH ₂ ) ₉ CH ₂ CO-DDab- Dab-Dab-Leu-DPhe-Dab-Dab- Leu-NHi NH ₂ NH ₂ 9 - and? [ ^{0 0} I ^c k. O 0 0 J 0 L nh ₂ I NH ₂ I 2 d-hCCH^CFLCO-DDab- Dab-Dab-Leu-DPhe-Dab-Dab- Leu-NHj NH, NH ₂ NH ₂ and? : And? fi? A^ O f O ^O [A ^O ΧγΧ ° 0 k. I nh ₂ I 3 CH ₃ (CH ₂ ) ₃ CH ₂ CH(CH ₃ )CH ₂ CH ₂ CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ ^nh ₂ NH; ⁰ |A ⁰ o A 0 L nh ₂ and nh ₂ ।

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Preferred branched lipopeptides of the present invention can be represented by the following formula

H-Dab(FA-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (SEQ ID NO: 4), wherein FA is a linear or branched fatty acid residue selected from the group consisting of n-dodecanoic acid, n-decanoic acid, 4-methylnonanoic acid and 4-methylhexanoic acid. The detailed structures of the more preferred branched lipopeptides of the invention are shown in Table 2.

Table 2. Branched lipopeptides

No. Model Lipopeptide short formula Structural formula 4 H-Dab(CH ₃ (CH ₂ )9CH ₂ CO-DDab)- Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ 1ΡΊ T ² opo Α'Ά o Z' ¹ a P ° V ° P ° V । MH ₂ 1 h ₂ n'^- ^a 'nh ---'ν'Χ 5 H-Dab(CH ₃ (CH ₂ ) ₇ CH ₂ CO-DDab)- Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ NH ₂ nh ₂ and? [ O < ° \ ⁰ Γ> coo ί,- O^NH 1 NH _Z 1 6 H- Dab(CH ₃ (CH ₂ ) ₃ CH ₂ CH(CH ₃ )CH ₂ CH ₂ CO-DDab)-Dab-Leu-DPhe- Dab-Dab-Leu-NH ₂ NH ₂ NH, = r ¹ o AA A » 'ΑΫΑνΆγΑ» ^{0 0} <y- O^NH 1 NH ₂ 1 η _ξ ν'^·'··^νη 7 H-Dab(CH ₃ CH ₂ CH(CH ₃ )CH ₂ CH ₂ C O-DDab)-Dab-Leu-DPhe-Dab-DabLeu-NH ₂ nh ₂ o < O AA OA 0 P ⁰ Y ° P ⁰ Y O^NH । NH _Z 1 HjN—Άη

The lipopeptides of the invention may be obtained by any synthetic method known in the art. For example, said synthetic method may comprise liquid phase synthesis or solid phase synthesis (see, e.g., Sewald, N. and Jakubko, H.-D. (2003), Peptide Synthesis. In Peptides: Chemistry and Biology (eds N. Sewald and H.-D. Jakubko) doi:10.1002/352760068X.ch4 and Peptide synthesis and applications, ed. / Knud J. Jensen; Pernille T. Shelton; Søren L. Pedersen. Humana Press, 2013, (Methods in Molecular Biology, Vol. 1047). An exemplary method for preparing the lipopeptides of the invention is provided in the Examples section below.

The lipopeptides of the invention, both linear and branched, have an amphiphilic structure and, due to the presence of 2,4-diaminobutyric acid residues, under physiological pH conditions (approximately 7.4) they have an excess positive charge, which facilitates their interaction with the bacterial cell membrane.

The pharmaceutical composition of the invention comprises any linear or branched lipopeptide of the invention, preferably selected from the group of lipopeptides of the formulae 1-7. Preferably, the composition comprises from 0.1 to 99 wt.% of any, at least one lipopeptide of the invention, preferably selected from the group consisting of lipopeptides of the formulae 1-7. The pharmaceutical composition may comprise at least one pharmaceutically acceptable carrier and/or diluent and/or adjuvant and/or excipient as known in the art. For example, but not limited to, the pharmaceutical composition may comprise corn starch, and/or gelatin, and/or lactose, and/or sucrose, and/or microcrystalline cellulose, and/or kaolin, and/or mannitol, and/or dicalcium phosphate, and/or sodium chloride, and/or alginic acid. Methods of preparing pharmaceutical compositions comprising an active agent, such as an antibacterial agent, and at least one pharmaceutically acceptable carrier, and/or diluent, and/or adjuvant, and/or excipient, are known in the art.

Preferably, the pharmaceutical composition of the invention further comprises at least one other antibacterial agent, such as an antibiotic. Exemplary antibacterial agents which may be a component of the pharmaceutical composition of the invention may be selected, among others, from: β-lactam antibiotics: such as e.g. penicillins, cephalosporins; peptide antibiotics, such as e.g. polymyxins (e.g. colistin), gramicidin, bacitracin, fusafungine; glycopeptide antibiotics: such as e.g. vancomycin, oritavancin; aminoglycoside antibiotics: such as e.g. streptomycin, gentamicin, amikacin; tetracycline antibiotics: such as e.g. doxycycline; macrolide antibiotics: such as e.g. erythromycin, clarithromycin; lincosamide antibiotics: such as e.g. clindamycin, lincomycin; amphenicol antibiotics: such as, for example, chloramphenicol; rifamycin antibiotics: such as, for example, rifampicin and rifaximin. Such combined use of at least two antibacterial agents with a different mechanism of action provides the additional advantage of obtaining a synergistic antibacterial effect. As is known from the literature, lipopeptides, such as polymyxins, provide a synergistic antibacterial effect in combination with other antibiotics (e.g. Berditsch et al. Antimicrob Agents Chemother. 59 (2015) 5288-5296 or Varra, M. Molecules 24 (2019) 249). Therefore, the use of lipopeptides according to the invention in combination with another antibacterial agent, such as an antibiotic, will provide a synergistic antibacterial effect.

Preferably, the pharmaceutical composition according to the invention is in a form suitable for oral and/or intravenous and/or intramuscular and/or subcutaneous and/or parenteral administration, preferably in the form of a tablet and/or capsule and/or elixir and/or suspension and/or syrup and/or gel and/or cream and/or ointment. Methods for preparing such forms of pharmaceutical compositions are known in the art of the present invention.

The cosmetic composition according to the invention comprises any linear or branched lipopeptide according to the invention, preferably selected from the group consisting of lipopeptides of abbreviated formulae 1-7. The cosmetic composition according to the invention may be in any cosmetically acceptable application form. The cosmetic composition may contain from 0.1 to 99% by weight of any at least one lipopeptide according to the invention, preferably selected from the group consisting of lipopeptides of abbreviated formulae 1-7. Preferably, the cosmetic composition according to the invention optionally comprises a cosmetic carrier. Cosmetic carriers are known in the art. For example, semi-solid or liquid polyols, as well as fats, e.g. in the form of micelles or liposomes, may be used as a cosmetic carrier. Preferably, the cosmetic composition is in the form of a gel, cream or suspension. Methods for preparing cosmetic compositions are known in the art.

The invention also includes synthetic, linear and branched, lipopeptides according to the invention, preferably of the abbreviated formulae 1-7, for use as a medicament. Preferably, the invention also includes synthetic, linear and branched, lipopeptides according to the invention, preferably of the abbreviated formulae 1-7, for use in the treatment of bacterial infections, preferably caused by gram-positive bacteria, more preferably of the Staphylococcus genus.

The synthetic, linear and branched, lipopeptides according to the invention are intended for use in the treatment and/or prophylaxis of bacterial infections due to their activity inhibiting the growth of gram-positive bacteria, preferably of the genus Enterococcus or Staphylococcus, more preferably of the species Staphylococcus aureus and Staphylococcus epidermidis, and gram-negative bacteria, preferably of the genus Klebsiella or Pseudomonas, more preferably of the species Klebsiella pneumoniae and Pseudomonas aeruginosa.

They are particularly active against bacteria of the Staphylococcus genus, as well as Pseudomonas and Klebsiella, especially Staphylococcus aureus and Staphylococcus epidermidis, as well as Klebsiella pneumoniae and Pseudomonas aeruginosa.

The advantage of the synthetic, linear and branched lipopeptides of the invention is their mechanism of action, which is based on direct interaction with the bacterial cell membrane, which in turn reduces the risk of drug resistance. Due to a different mechanism of action than antibiotics known in the art, the lipopeptides of the invention will be effective against bacteria resistant to antibiotics with a different mechanism of action than the lipopeptides of the invention. Additionally, the synthetic, linear and branched lipopeptides of the invention are simple and easy to synthesize structures, which significantly reduces their production cost. The synthetic, linear and branched lipopeptides of the invention are also characterized by appropriate solubility in an aqueous environment, which significantly broadens the range of possibilities regarding the application form of the pharmaceutical or cosmetic composition of the invention. The synthetic, linear and branched lipopeptides of the invention are also characterized by increased metabolic stability, which provides an additional advantage in the form of a significant extension of their duration of action, and thus additionally increases their effectiveness.

For the purpose of illustrating the invention, examples and drawings are included below, which, however, should not be construed as in any way limiting the scope of the invention, which is defined in the claims. The accompanying drawings illustrate preferred embodiments of the invention.

Figure 1 shows an exemplary scheme for the preparation of a synthetic linear lipopeptide according to the invention (abbreviated formula 2).

Figure 2 shows an exemplary scheme for the preparation of a synthetic branched lipopeptide according to the invention (abbreviated formula 5).

Figure 3 shows the effect of the lipopeptide of truncated formula 1 according to the invention on the growth dynamics of Pseudomonas aeruginosa (panel A) and Staphylococcus aureus (panel B) strains, presented as the relative optical density of the cultures as a function of time.

Figure 4 shows the effect of the lipopeptide of truncated formula 2 according to the invention on the growth dynamics of Pseudomonas aeruginosa (panel A) and Staphylococcus aureus (panel B) strains, presented as the relative optical density of the cultures as a function of time.

Figure 5 shows the effect of the lipopeptide of truncated formula 3 according to the invention on the growth dynamics of Pseudomonas aeruginosa (panel A) and Staphylococcus aureus (panel B) strains, presented as the relative optical density of the cultures as a function of time.

Figure 6 shows the effect of the reference lipopeptide on the growth dynamics of Pseudomonas aeruginosa (panel A) and Staphylococcus aureus (panel B) strains, presented as the relative optical density of the cultures as a function of time.

Unless otherwise indicated, the following examples use known and/or commercially available devices, methods, reaction conditions, reagents and kits, such as are commonly used in the art to which the present invention pertains and as recommended by the manufacturers of the corresponding reagents and kits.

EXAMPLE 1. Synthesis of lipopeptides according to the invention

Lipopeptides, both linear and branched, were obtained by Solid Phase Peptide Synthesis using the Fmoc/tBu synthesis strategy on a polymeric support, which was Fmoc-Rink Amide AM resin (loading 0.55 mmol/g, Activotec, UK). The synthesis was started by weighing 365 mg of resin and placing it in a syringe reactor, then 5 ml of N,N-dimethylformamide (DMF, Sigma-Aldrich) was added and shaken for 2 h to swell the resin. The following steps were then carried out:

1. Deprotection of the Fmoc (9-fluorenylmethoxycarbonyl) shield blocking the amino group.

For this purpose, the resin was shaken twice (1 x 5 min, 1 x 10 min) in a 20% (v/v) piperidine solution in DMF. To remove residual piperidine, the resin was washed alternately with DMF and isopropanol (IPA, POCH S.A., Poland). The procedure was repeated three times, after which the polymer support was washed twice more with DMF (each time: 5-6 ml, 2 min/wash).

2. The Kaiser test was used to assess the effectiveness of the Fmoc-deprotection step. The standard procedure for performing this test was to suspend a sample of resin grains in a mixture of solutions A-C (3-5 drops of each) and heat at approximately 100°C; using the starting solutions of the following composition: 5 g of ninhydrin in 100 ml of ethanol (solution A); 80 g of phenol in 20 ml of ethanol (solution B); 2 ml of 0.001 M aqueous solution of KCN in 98 ml of pyridine (solution C). The navy blue color of both the grains and the solution indicated the presence of a free amino group.

3. The next step was to carry out the condensation reaction between the amino acid derivative (Fmoc-Xaa)-OH and the amino group of the resin. For this purpose, the appropriate amounts of reagents were weighed and measured into the vessel (molar ratio relative to the resin population):

- 2 equivalents of the appropriate amino acid derivative Fmoc Xaa-OH,

- 2 equivalents of DIC (N,N'-Diisopropylcarbodiimide) coupling agent,

- 2 equivalents of Oxyma anti-racemization reagent.

Then, the above-mentioned reagents were dissolved in 3-4 ml of DMF and left for about 10 minutes, after which the mixture prepared in this way was transferred to a syringe reactor with resin and mixed/shaken for about 4-6 hours. After this time, the reaction mixture was filtered and the resin was washed alternately with DMF and IPA, starting with DMF (2 x, each time: 5-6 ml, 2 min/wash).

4. Then the Kaiser test was performed (according to point no. 2), this time to assess the progress/completion of the condensation reaction. A negative test result, i.e. no coloration of the grains or solution, indicated complete attachment of the Fmoc-protected amino acid to the resin, i.e. completion of the condensation reaction. If the test result was positive, the amino acid derivative coupling step was repeated using a double excess of reagents (the molar ratio of Fmoc-Xaa-OH/DIC/Oxyma was 1:1:1).

5. Cyclic repetition of the steps described in points 1-4 led to the elongation of the peptide chain. In the case of the condensation steps of individual amino acid residues to peptidyl resin, the standard building blocks used in the Fmoc/iBu synthesis strategy were used, i.e.: Fmoc-Leu-OH, Fmoc-DPhe-OH, Fmoc-Dab(Boc)-OH, Fmoc-DDab(Boc)-OH, and in the case of branched analogues of the Boc-Dab(Fmoc)-OH derivative at the penultimate condensation reaction stage (FmocXaa-OH, Activotec, Great Britain).

6. The penultimate step of the synthesis was the addition of a fatty acid (R-COOH, Merck).

For this purpose - after prior deprotection of the α-amino protecting group and confirmation of the presence of a free amine group in the Kaiser test - the following amounts of reagents were weighed into the vessel:

- 2 equivalents of a given fatty acid,

- 2 equivalents of DIC coupling agent,

- 2 equivalents of Oxyma anti-racemization reagent.

Then, the above-mentioned reagents were dissolved in 3-4 ml of DMF/DCM (1:1, v/v, DCM = dichloromethane) and left for about 10 minutes. The mixture prepared in this way was transferred to a syringe reactor with resin and shaken for about 24 hours to attach the fatty acid. After the reaction was completed (detection by Kaiser test), the resins were washed first 4 times with DMF/DCM (1:1, v/v) and then 4 times with each of the following solvents (2 min/wash):

- dichloromethane,

- methanol,

- diethyl ether.

The washed peptidyl resins were then dried in a vacuum desiccator for 30 min.

7. The final stage of the syntheses was the acidolytic cleavage of the peptide from the polymer support, in which Reagent B was used: TFA/H2O/phenol/TIPS (88:5:5:2, v/v), (where: TFA - trifluoroacetic acid, TIPS - triisopropylsilane). Reagent B was added to the dried peptidyl resin in a ratio of approx. 10 ml per 1 g of peptidyl resin. The mixture was shaken for 2-4 hours. After this time, the resin was filtered off, washed with an additional small portion of TFA, and the obtained filtrate was concentrated on an evaporator. The residue was covered with cold diethyl ether (cooled in dry ice) and left for 24 hours in a refrigerator to precipitate the peptide. Then, after 24 hours, the crude peptide was isolated by centrifugation.

8. Analytical HPLC was performed on a modular Prominence liquid chromatograph from

Shimadzu with DAD detector. A Luna 5 μm, C18 (2) 100A reversed phase column with dimensions of 250 x 4.6 mm was used. Semi-preparative RP-HPLC was performed on a Prominence LC-20AP modular liquid chromatograph with UV-VIS detector. A Luna 5 μm, C18, column with dimensions of 150 x 10 mm was used. Identification of the obtained lipopeptides was performed on the basis of mass spectra

PL 246720 Β1 performed on a Shimadzu LCMS-IT-TOF instrument equipped with an electrospray ion source (ESI) with an ion trap (IT) and a time-of-flight (TOF) analyzer. Before proceeding to the purification stage of a given peptide, an RP-HPLC analysis of the crude product was performed in order to optimize the separation conditions for a given crude peptide mixture.

9. Due to the fact that the designed and synthesized peptides were to be subjected to biological studies, it was necessary to exchange the counterion from trifluoroacetate (TFA ) to chloride (Cl ). For this purpose, the purified peptide was dissolved in 0.1 M hydrochloric acid solution, then stirred for 30 min., then concentrated on an evaporator and the residue was frozen and lyophilized. This procedure was repeated several times (usually 3-4) until the mass of the weighed material did not change any more. An example scheme of the synthesis of a linear lipopeptide (No. 2) and a branched lipopeptide (No. 5) is shown in Figures 1 and 2, respectively.

EXAMPLE 2. Study of the biological activity of lipopeptides according to the invention

Bacterial strains and culture media

All bacterial strains were obtained from the Polish Collection of Microorganisms (PCM) or the American Type Culture Collection (ATCC). Gram-positive bacterial strains: Staphylococcus aureus ATCC 29213, Staphylococcus epidermidis ATCC 12228, and Enterococcus faecalis ATCC 14506. Gram-negative bacterial strains: Escherichia coliST2-8624 O157:H7, Pseudomonas aeruginosa PAO1 PCM 499, Klebsiella pneumoniae PCM 1, Salmonella sv. Typhimurium TT622, and Yersinia enterocolitica PCM 2081. All strains were cultured in LB (lysogenic broth) in a standard manner.

The structure of the tested lipopeptides according to the invention

Biological activity was tested for lipopeptides with truncated formulas 1-7, and the obtained results were compared with the activity of the prior art linear reference lipopeptide described in the publications by De Zoysa et al., European Journal of Medicinal Chemistry, 2018, 146, 344 and De Zoysa et al., Journal of Medicinal Chemistry, 2015, 58, 625. The structure of the peptide part of the reference lipopeptide is described by the formula:

4MH-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ wherein 4MH is a 4-methylhexanoic acid residue.

Determination of the Minimum Inhibitory Concentration (MIC)

Material from a single bacterial colony was inoculated into 10 ml of LB medium and grown at 30°C with shaking overnight. The optical density of the overnight cultures (at a wavelength of 600 nm) was then adjusted to 0.05 by dilution in a fresh portion of LB medium. The compounds to be tested were dissolved in water. Serial dilutions of the compounds were prepared in LB medium ranging from 5 to 50 pg/ml (final concentrations). The experiment was performed by adding 100 µl of each of the prepared dilutions to 100 µl of a diluted overnight culture of bacteria in the wells of a 96-well microtiter plate. The MIC was defined as the lowest concentration of the test compound required to inhibit bacterial growth assessed after 24 h of incubation at 30°C with shaking (final optical density at a wavelength of 600 nm not greater than 0.05). Optical density measurements were performed using a TECAN Sunrise plate reader. Data were obtained from three independent experiments. The results are summarized in Table 3.

Table 3

MIC [pg/ml = mg/l] Reference lipopeptide n.d. 40 n.d. 50 n.d. 15c n.d. n.d. 50 c n.d. n.d. n.d. n.d. c: 20 About m 30 n.d. Oh 20 n.d. Lfl 50 10 Oh 20 n.d. LO Oh -Oh Tf 30 oz 20 Oh n.d. LO LO n.d. ro n.d. 20 o o n.d. Oh Oh n.d. Γ4 n.d. 10 n.d. 20 40 10 LO n.d. 40 40 o o n.d. lh LH "6c Bacterial strain (+) Enterococcus faecalis ATCC 14506 (-) Escherichia coli ST2-8624 O157:H7 (-) Klebsiella pneumoniae PCM 1 (-) Pseudomonas aeruginosa PAO1 PCM 499 (-) Salmonella sv. Typhimurium TT622 (+) Staphylococcus aureus ATCC 29213 (+) Staphylococcus epidermidis ATCC 12228 (-) Yersinia enterocoiitica PCM 2081

n.d. = not determined, i.e. the MIC value was higher than 50 pg/ml

The measurement results presented in Table 3 indicate that all of the tested lipopeptides demonstrate varied activity against the tested bacterial strains. The lipopeptides according to the invention demonstrate activity against both gram-positive and gram-negative bacterial strains. The reference lipopeptide, which is not the subject of the invention and is included in the table for comparative purposes only, demonstrates low activity against only two of the eight analyzed bacterial strains. The obtained results indicate a certain degree of selectivity of the lipopeptides according to the invention against the gram-positive strains of Staphylococcus aureus ATCC 29213, Staphylococcus epidermidis ATCC 12228, in the case of which the highest activity of the tested lipopeptides was observed, i.e. the lowest values of the minimum inhibitory concentration (MIC). At the same time, the activity of the tested lipopeptides against the strains of Yersinia enterocolitica PCM 2081 and Salmonella sv. Typhimurium TT622 is negligible.

Determination of the effect of lipopeptides on bacterial growth dynamics

The effect of different concentrations of lipopeptides with abbreviated formulas 1-3 according to the invention and a reference lipopeptide on bacterial growth was checked for one representative strain of gram-negative bacteria: Pseudomonas aeruginosa PAO1 PCM 499 and one representative strain of gram-positive bacteria: Staphylococcus aureus ATCC 29213. The experiment was carried out analogously to the MIC determination, but in this case the diluted overnight cultures were preincubated for 2 h before adding the diluted lipopeptides. Then the bacterial growth was monitored by measuring the optical concentration of the culture at a wavelength of 600 nm every 60 min for 6 h. Data were obtained from three independent experiments. The measurement results are presented in the form of graphs presented in Figures 3-6.

The obtained results show that the tested lipopeptides according to the invention significantly slow down the growth dynamics of bacteria, both gram-positive and gram-negative. For the bacterial strains Pseudomonas aeruginosa PAO1 PCM 499 and Staphylococcus aureus ATCC 29213, lipopeptide concentrations of 5.0 mg/l caused almost complete inhibition of bacterial growth. In the case of the reference lipopeptide, its effect on the growth dynamics of both tested bacterial strains was definitely weaker than that observed for lipopeptides with truncated formulas 1-3 according to the invention.

Measurement of enzymatic degradation of lipopeptides in human blood serum

Peptide degradation measurements in human blood serum were performed on peptide stock solutions with Z-Val-OH added as internal standard. To prepare stock solutions:

• peptide samples were weighed;

• an internal standard solution (Z-Val-OH) was prepared at a concentration of 60 μmol/ml, where the solvent was H2O/ACN 30:70 (v/v);

• then, stock solutions of each of the tested lipopeptides were prepared at a concentration of 70 μmol/ml by dissolving previously weighed portions of the compounds in the appropriate volume of internal standard solution.

The measuring systems were mixed at 37°C at 450 rpm using an Eppendorf Thermomixer R. The protocol for measuring lipopeptide degradation in human blood serum included:

1. Adding 10 μl of peptide stock solution to 690 μl of human blood serum previously incubated at 37°C for 10 minutes (Thermomixer).

2. 15 second mixing (Vortex) of the serum-peptide mixture.

3. Collection of 50 μl sample - after the selected time interval.

4. Adding 200 μl of serum deactivation system (ACN : H2O : FA 89 : 10 : 1 v/v/v).

5. 20 second mixing (Vortex).

6. Cool for 20 minutes at 4°C.

7. 15 minutes centrifugation at 4°C (14000 rpm).

8. Collection of 150 μl of supernatant.

9. Add 300 μl of water (milliQ grade) to the supernatant collected in point 8.

10. Freeze-drying the sample.

11. Dissolve the lyophilisate in 150 μl of a solution of ACN : H2O : FA 20 : 80 : 0.1 v/v/v.

12. Exposing the sample to ultrasound and mixing for 10 seconds (Vortex).

13. 4 minute spin (14000 rpm).

14. Collection of 120 μl of supernatant.

15. Carrying out the HPLC measurement (10 μ^ sample injection).

16. Repeat the process three times for all 8 peptides.

PL 246720 Β1

17. For HPLC-MS analyses, the injection was 2 pl - measurements were made for degradation times of 48 and 96 hours.

The results of lipopeptide degradation measurements in blood serum are presented in Table 4, where the half-life of the starting substrate (ti/2) is given.

Table 4.

Model No. Lipopeptide short formula Half-life (ti/ ₂ ) in hours 1 CH ₃ (CH ₂ ),CH ₂ CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ 49 2 CH ₃ (CH ₂ ) ₇ CH ₂ CO-DDab-Dab-Dab-Leu-DPhe- Dab-Dab-Leu-NH ₂ 37 3 CH ₃ (CH ₂ ) ₃ CH ₂ CH (CH ₃ )CH ₂ CH ₂ CO-DDab- Dab-Dab-Leu-DPhe-Dab-Dab-Leu-Nhh 35 4 H-Dab(CH ₃ (CH ₂ ) ₉ CH ₂ CO-DDab)-Dab-Leu- DPhe-Dab-Dab-Leu-NH ₂ 56 5 H-Dab(CH ₃ (CH ₂ ) ₇ CH ₂ CO-DDab)-Dab-Leu- DPhe-Dab-Dab-Leu-NH ₂ 41 6 H Dab(CH ₃ (CH ₂ ) ₃ CH ₂ CH(CH ₃ )CH ₂ CH ₂ CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NI4 ₂ 48 7 H-Dab(CH ₃ CH ₂ CH(CH ₃ )CH ₂ CH ₂ CO-DDab)- Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ 29 Reference lipopeptide CH ₃ CH ₂ CH(CH ₃ )CH ₂ CH ₂ CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ 27

All of the lipopeptides tested according to the invention are subject to enzymatic degradation in human blood serum, however, they are characterized by increased metabolic stability and their half-life times are above 27 hours, which is the time observed for the reference lipopeptide. The shortest time is characterized by lipopeptides containing the shortest fatty acid chains. All of the lipopeptides according to the invention are characterized by a longer half-life than the reference lipopeptide, however, and are therefore characterized by increased metabolic stability.

PL 246720 Β1

Sequence list <110> University of Warsaw <120> Lipopeptides having antibacterial activity, pharmaceutical and cosmetic compositions containing such lipopeptides and uses <130> 17P46496PL00 <160> 4 <170> BiSSAP 1.3,6 <210> 1 <211> 8 <212> PRT < 213> Artificial sequence <220>

< 223> Synthetic linear lipopeptide with the general formula

X1-Dab-X2-X3-Dab-Dab-X4-NH2, where X1 is

FA-DDab-Dab <220>

< 221> MUTAGEN < 222> 1..1 <223> X denotes D-Dab with a fatty acid residue attached <220>

<221> YARIANT <222> 2..2 <223> X means Dab <220>

<221> VARIANT <222> 3..3 <223> X means Dab <220>

<221> VARIANT

PL 246720 Β1 <222> 4..4 <223> X means Leu, Ile. Ala or Val <220>

< 221> YARIANT < 222> 5..5 < 223> X means D-Phe, D-Tyr or D-Trp <220>

< 221> YARIANT < 222> 6..6 < 223> X means Dab < 220>

< 221> VARIANT < 222> 7..7 < 223> X means Dab <220>

< 221> VARIANT < 222> 8..8 < 223> X means Leu, Ile, Ala or Val < 400> 1

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

5 <210> 2 <211> 8 <212> PRT <213> Artificial sequence <220>

< 223> Synthetic linear lipopeptide with the general formula

X1-Dab-X2-X3-Dab-Dab-X4-NH2, where X1 is

PL 246720 Β1

FA-DDab-Dab <220>

<221> MUTAGEN <222> 1..1 <223> X denotes D-Dab with a fatty acid residue attached <220>

<221> YARIANT <222> 2..2 <223> X means Dab <220>

<221> VARIANT <222> 3..3 <223> X means Dab <220>

<221> VARIANT <222> 5..5 <223> X means D-Phe <220>

<221> VARIANT <222> 6..6 <223> X6 means Dab <220>

<221> VARIANT <222> 7..7 <223> X means Dab <400> 2

PL 246720 Β1

Xaa Xaa Xaa Leu Xaa Xaa Xaa Leu

5 <210> 3 <211> 8 <212> PRT <213> Artificial sequence <220>

< 223> Synthetic branched lipopeptide of the general formula X1-Dab-X2-X3-Dab-Dab-X4-NH2, wherein X1 is H-Dab(FA-DDab) <220>

< 221> VARIANT < 222> 1..1 < 223> X denotes H-Dab <220 < 221> MUTAGEN < 222> 2..2 < 223> X denotes D-Dab with a fatty acid residue attached <220 <221> VARIANT < 222> 3..3 < 223> X denotes Dab <220>

< 221> VARIANT < 222> 4..4 < 223> X stands for Leu, Ile, Ala or Val

PL 246720 Β1 <220>

<221> VARIANT <222> S..S <223> X means D-Phe, D-Tyr or D-Trp <220 <221> VARIANT <222> 6..6 <223> X means Dab <220>

< 221 > VARIANT < 222> 7..7 < 223> X means Dab <220 < 221> VARIANT < 222> 8..8 < 223> X means Leu, Ile, Ala or Val < 400> 3

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

5 <210> 4 <211> 8 <212> PRT <213> Artificial sequence <220>

< 223> Synthetic branched lipopeptide of the general formula X1-Dab-X2-X3-Dab-Dab-X4-NH2, wherein X1 is H-Dab(FA-DDab)

PL 246720 Β1 <220 <221> VARIANT <222> 1..1 <223> X denotes H-Dab <220 <221> MUTAGEN <222> 2..2 <223> X denotes D-Dab with a fatty acid residue attached <220 <221> VARIANT <222> 3..3 <223> X denotes Dab <220 <221> VARIANT <222> 5..5 <223> X denotes D-Phe, D-Tyr or D-Trp <220 <221> VARIANT <222> 6..6 <223> X denotes Dab <220>

<221> VARIANT <222> 7..7 <223> X means Dab <400 4

Xaa Xaa Xaa Leu Xaa Xaa Xaa Leu

PL 246720 Β1

Claims (33)

Patent Claims 1. Synthetic lipopeptide with the general formula: Xi-Dab-X ₂ -X ₃ -Dab-Dab-X ₄ -NH ₂ in which Xi is a residue selected from FA-DDab-Dab and H-Dab(FA-DDab), wherein when Xi is FA-DDab-Dab then FA is a residue of a fatty acid selected from the group consisting of n-dodecanoic acid, n-decanoic acid and 4-methylnonanoic acid, and when Xi is H-Dab(FA-DDab) then FA is a residue of a fatty acid selected from the group consisting of n-dodecanoic acid, n-decanoic acid and 4-methylnonanoic acid; Χ2 denotes a leucine, alanine, isoleucine or valine residue; Χ3 represents a D-phenylalanine, D-tyrosine or D-tryptophan residue; and Χ4 represents a leucine, alanine, isoleucine or valine residue. 2. The lipopeptide according to claim 1, wherein Χ1 is FA-DDab-Dab, Χ2 is a leucine residue, Χ3 is a D-phenylalanine residue, and Χ4 is a leucine residue. 3. The lipopeptide of claim 2, wherein the lipopeptide is selected from the group consisting of: CH3(CH2) ₄ CH2CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH2(short formula 1), CHifCHijyCHiCO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NFbfshort formula 2), and CHsfCHijiCHiCHfCHijCHiCHiCO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH? (short formula 3). 4. The lipopeptide of claim 1, wherein Xi is H-Dab(FA-DDab), Χ2 is a leucine residue, Χ3 is a D-phenylalanine residue, and Χ4 is a leucine residue. 5. The lipopeptide of claim 4, wherein the lipopeptide is selected from the group consisting of: H-Dab(CH ₃ (CH2)>>CH2CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH2 (shortened formula 4), H-Dab(CH ₃ (CH ₂ ) ₇ CH 2 CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH 2 (shortened formula 5), and H-Dab(CH3(CH2)3CH2CH(CH3)CH2CH2CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH2 (shortened formula 6). 6. A pharmaceutical composition characterized in that it comprises a lipopeptide of the general formula: Xi-Dab-X ₂ -X ₃ -Dab-Dab-X4-NH2 in which Χ1 denotes a residue selected from FA-DDab-Dab and H-Dab(FA-DDab), wherein when Χ1 denotes FA-DDab-Dab then FA denotes a residue of a fatty acid selected from the group consisting of n-dodecanoic acid, n-decanoic acid and 4-methylnonanoic acid, when Χ1 denotes H-Dab(FA-DDab) then FA denotes a residue of a fatty acid selected from the group consisting of n-dodecanoic acid, n-decanoic acid and 4-methylnonanoic acid; Χ2 denotes a leucine, alanine, isoleucine or valine residue; Χ3 denotes a D-phenylalanine, D-tyrosine or D-tryptophan residue Χ4 denotes a leucine, alanine, isoleucine or valine residue. 7. The pharmaceutical composition according to claim 6, characterized in that in the lipopeptide Χ1 is FA-DDab-Dab, Χ2 is a leucine residue, Χ3 is a D-phenylalanine residue, and Χ4 is a leucine residue. 8. The pharmaceutical composition of claim 7, wherein the composition comprises a lipopeptide selected from the group consisting of: CH ₃ (CH2)9CH ₂ CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH2 (short formula 1), CHsiCHiJyCHiCO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NHi (short formula 2), and CH ₃ (CH2)3CH2CH(CH ₃ )CH2CH2CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH2 (shortened formula 3). PL 246720 Β1 9. The pharmaceutical composition according to claim 6, characterized in that in the lipopeptide X1 is H-Dab(FA-DDab), Χ2 is a leucine residue, Χ3 is a D-phenylalanine residue, and Χ4 is a leucine residue. 10. The pharmaceutical composition of claim 9, wherein the composition comprises a lipopeptide selected from the group consisting of: H-Dab(CH ₃ (CH2),CH ₂ CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH2 (shortened formula 4), H-DabfCH^Cl-hjyCHjCO-DDabj-Dab-Leu-DPhe-Dab-Dab-Leu-NHj (abbreviated formula 5), and H-Dab(CH ₃ (CH ₂ ) ₃ CHiCH(CH ₃ )CHiCH ₂ CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leij-NI-li (abbreviated formula 6). 11. A pharmaceutical composition according to any one of claims 6 to 10, characterized in that it comprises from 0.1 to 99% by weight of at least one lipopeptide. 12. A pharmaceutical composition according to any one of claims 6 to 11, characterized in that it comprises a pharmaceutically acceptable carrier and/or a diluent and/or an adjuvant and/or an excipient. 13. Pharmaceutical composition according to claim 12, characterized in that it comprises corn starch and/or gelatin and/or lactose and/or sucrose and/or microcrystalline cellulose and/or kaolin and/or mannitol and/or dicalcium phosphate and/or sodium chloride and/or alginic acid. 14. A pharmaceutical composition according to any one of claims 6 to 13, characterized in that it is in a form suitable for oral and/or intravenous and/or intramuscular and/or subcutaneous and/or parenteral administration. 15. A pharmaceutical composition according to any one of claims 6 to 14, characterized in that it is in the form of a tablet and/or a capsule and/or an elixir and/or a suspension and/or a syrup and/or a gel and/or a cream and/or an ointment. 16. Cosmetic composition characterized in that it contains a lipopeptide of the general formula: Xi-Dab-X ₂ -X3-Dab-Dab-X ₄ -NH2 in which Χ1 is selected from FA-DDab-Dab and H-Dab(FA-DDab), wherein when Χ1 is FA-DDab-Dab then FA is a fatty acid residue selected from the group consisting of n-dodecanoic acid, n-decanoic acid and 4-methylnonanoic acid, when Χ1 is H-Dab(FA-DDab) then FA is a fatty acid residue selected from the group consisting of n-dodecanoic acid, n-decanoic acid, 4-methylnonanoic acid and 4-methylhexanoic acid; Χ2 denotes a leucine, alanine, isoleucine or valine residue; Χ3 denotes a D-phenylalanine, D-tyrosine or D-tryptophan residue Χ4 denotes a leucine, alanine, isoleucine or valine residue. 17. The cosmetic composition according to claim 16, characterized in that in the lipopeptide Χ1 denotes FA-DDab-Dab, Χ2 denotes a leucine residue, Χ3 denotes a D-phenylalanine residue and Χ4 denotes a leucine residue. 18. The cosmetic composition according to claim 17, characterized in that it comprises a lipopeptide selected from the group consisting of: CHj/CHijiCHiCO-DDab-Dab-Dab-Leij-DPhe-Dab-Dab-Leu-NHif (abbreviated formula 1), Cl-h(CH ₂ )7CH2CO-DDab-Dab-Dab-LeLi-DPhe-Dab-Dab-LeLi-NH ₂ (abbreviated formula 2), and CH^CHiJsCHiCHiCI-hjCHiCHiCO-DDab-Dab-Leij-DPhe-Dab-Dab-Leu-NI-h (abbreviated formula 3). 19. The cosmetic composition according to claim 16, characterized in that in the lipopeptide Χ1 is H-Dab(FA-DDab), Χ2 is a leucine residue, Χ3 is a D-phenylalanine residue and Χ4 is a leucine residue. 20. The cosmetic composition according to claim 19, characterized in that it comprises a lipopeptide selected from the group consisting of: PL 246720 Β1 H-Dab(CH ₃ (CH ₂ )tiCH ₂ CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (abbreviated formula 4), H-Dab(CH ₃ (CH ₂ )7CH ₂ CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (abbreviated formula 5), H-Dab(CH ₃ (CH ₂ ) ₃ CH ₂ CH(CH ₃ )CH ₂ CH ₂ CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (abbreviated formula 6), and H-Dab(CH ₃ CH ₂ CH(CH ₃ )CH ₂ CH ₂ CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (short formula 7). 21. The cosmetic composition according to any one of claims 16 to 20, characterized in that it comprises from 0.1 to 99% by weight of at least one lipopeptide. 22. The cosmetic composition of any one of claims 16 to 21, characterized in that it comprises a cosmetic carrier. 23. The cosmetic composition according to any one of claims 16 to 22, characterized in that it is in the form of a gel or cream or a suspension. 24. A lipopeptide as claimed in any one of claims 1 to 5 for use as a medicament. 25. A lipopeptide as claimed in any one of claims 1 to 5 for use in the treatment or prevention of a bacterial infection. 26. The lipopeptide for use according to claim 25, wherein the bacterial infection is caused by a gram-positive bacterium. 27. The lipopeptide for use according to claim 26, wherein the bacterial infection is caused by a bacterium of the genus Enterococcus or Staphylococcus. 28. The lipopeptide for use according to claim 27, wherein the bacterial infection is caused by Staphylococcus aureus or Staphylococcus epidermidis. 29. The lipopeptide for use according to claim 25, wherein the bacterial infection is caused by a gram-negative bacterium. 30. The lipopeptide for use according to claim 29, wherein the bacterial infection is caused by a bacterium of the genus Klebsiella or Pseudomonas. 31. The lipopeptide for use according to claim 30, wherein the bacterial infection is caused by Klebsiella pneumoniae or Pseudomonas aeruginosa. 32. The lipopeptide for use according to any one of claims 24 to 31, wherein the infection is caused by a bacterium resistant to an antibiotic or antibiotics. 33. The lipopeptide for use according to any one of claims 24 to 31, wherein at least one lipopeptide is used selected from the group consisting of: CH ₃ (CH ₂ )?CH ₂ CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (short formula 1), CH ₃ (CH ₂ )7CH ₂ CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (shortened formula 2), CH ₃ (CH ₂ ) ₃ CH ₂ CH(CH ₃ )CH ₂ CH ₂ CO-DDab-Dab-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (abbreviated formula 3), H-Dab(CH ₃ (CH ₂ )9CH ₂ CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NI-l ₂ (abbreviated formula 4), H-Dab(CH ₃ (CH ₂ )7CH ₂ CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (abbreviated formula 5), and H-Dab(CH ₃ (CH ₂ ) ₃ CH ₂ CH(CH ₃ )CH ₂ CH ₂ CO-DDab)-Dab-Leu-DPhe-Dab-Dab-Leu-NH ₂ (shortened formula 6).