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Conjugation of fatty acids with different lengths modulates the antibacterial and antifungal activity of a cationic biologically inactive peptide.

ABSTRACT: Many studies have shown that an amphipathic structure and a threshold of hydrophobicity of the peptidic chain are crucial for the biological function of AMPs (antimicrobial peptides). However, the factors that dictate their cell selectivity are not yet clear. In the present study, we show that the attachment of aliphatic acids with different lengths (10, 12, 14 or 16 carbon atoms) to the N-terminus of a biologically inactive cationic peptide is sufficient to endow the resulting lipopeptides with lytic activity against different cells. Mode-of-action studies were performed with model phospholipid membranes mimicking those of bacterial, mammalian and fungal cells. These include determination of the structure in solution and membranes by using CD and ATR-FTIR (attenuated total reflectance Fourier-transform infrared) spectroscopy, membrane leakage experiments and by visualizing bacterial and fungal damage via transmission electron microscopy. The results obtained reveal that: (i) the short lipopeptides (10 and 12 carbons atoms) are non-haemolytic, active towards both bacteria and fungi and monomeric in solution. (ii) The long lipopeptides (14 and 16 carbons atoms) are highly antifungal, haemolytic only at concentrations above their MIC (minimal inhibitory concentration) values and aggregate in solution. (iii) All the lipopeptides adopt a partial alpha-helical structure in 1% lysophosphatidylcholine and bacterial and mammalian model membranes. However, the two short lipopeptides contain a significant fraction of random coil in fungal membranes, in agreement with their reduced antifungal activity. (iv) All the lipopeptides have a membranolytic effect on all types of cells assayed. Overall, the results reveal that the length of the aliphatic chain is sufficient to control the pathogen specificity of the lipopeptides, most probably by controlling both the overall hydrophobicity and the oligomeric state of the lipopeptides in solution. Besides providing us with basic important information, these new lipopeptides are potential candidates that can target bacteria and/or fungi, especially in cases where the bacterial flora should not be harmed.

SUBMITTER: Malina A

PROVIDER: S-EPMC1199663 | biostudies-other | 2005 Sep

REPOSITORIES: biostudies-other

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Project description:Nowadays, biomaterials are applied in many different branches of medicine. They significantly improve the patients' comfort and quality of life, but also constitute a significant risk factor for biofilm-associated infections. Currently, intensive research on the development of novel materials resistant to microbial colonization as well as new compounds that are active against biofilms is being carried out. Within this research, antimicrobial peptides (AMPs) and their analogues are being intensively investigated due to their promising antimicrobial activities. The main goal of this study was to synthesize and evaluate the antimicrobial efficacy of short cationic lipopeptides that were designed to imitate the features of AMPs responsible for antimicrobial activities: positive net charge and amphipacity. The positive charge of the molecules results from the presence of basic amino acid residues: arginine and lysine. Amphipacity is provided by the introduction of decanoic, dodecanoic, tetradecanoic, and hexadecanoic acid chains to the molecules. Lipopeptides (C16-KR-NH2, C16-KKK-NH2, C16-KKC-NH2, C16-KGK-NH2, C14-KR-NH2, C14-KKC-NH2, C12-KR-NH2, C12-KKC-NH2, and (C10)2-KKKK-NH2) were synthesized using a novel solid-phase temperature-assisted methodology. The minimum inhibitory concentrations (MICs), minimum biofilm eradication concentrations (MBECs), and minimum biofilm formation inhibitory concentrations (MBFICs) were determined for the following bacterial strains: Staphylococcus aureus ATCC 25923, Staphylococcus epidermidis ATCC 14990, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 9027, and Proteus mirabilis PCM 543. The biofilms were cultured on two types of surfaces: polystyrene plates (PS) and contact lenses (CL). The lipopeptides exhibited the ability to inhibit the growth of bacteria in a liquid medium as well as on the PS and CL. The compounds also eliminated the bacterial biofilm from the surface of both materials. In general, the activity against gram-positive bacteria was stronger in comparison to that against gram-negative strains. There were certain discrepancies between the activity of compounds against the biofilm cultured on PS and CL. This was especially noticeable for staphylococci-the lipopeptides presented much higher activity against biofilm formed on the PS surface. It is worth noting that the obtained MBEC values for lipopeptides were usually only a few times higher than the MICs. The results of the performed experiments suggest that further studies on lipopeptides and their potential application in the treatment and prophylaxis of biofilm-associated infections should be conducted.

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Conjugation of fatty acids with different lengths modulates the antibacterial and antifungal activity of a cationic biologically inactive peptide.

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