pH-Dependent Antifungal Lipopeptides and Their Plausible Mode of Action

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Abstract
Antimicrobial peptides and lipopeptides play an essential protective role in the innate immune system of all organisms. Despite many studies, the factors that dictate their cell-selectivity and pH-dependent activity are yet not clear. This is important because various organs of the human body have an acidic pH environment, for example, the vagina, gastric lumen, cryogenic dental foci, and lung-lining fluids in cystic fibrosis and asthma. In this study we synthesized a new group of lipopeptides by conjugating dodecanoic acid (DDA) to the N-termini of 12-mer peptides LXXLLXXLLXXL (L6X6, X = Lys, His, Arg, and all the leucines are d-amino acid enantiomers) and investigated their pH-dependent biological activity and a plausible mode of action by using model phospholipids mimicking bacterial, mammalian, and fungal membranes. The data revealed that, depending on the basic amino acid incorporated, the lipopeptides are active against both bacteria and fungi or solely toward fungi. Furthermore, their activity is expressed at an acidic pH alone, neutral pH alone, or at both environments. Determination of secondary structure, membrane leakage experiments, surface plasmon resonance (SPR) binding experiments, and transmission electron microscopy suggest the involvement of a membranolytic effect. This mode of action, which should make it hard for the microorganism to develop resistance, their selective and pH-dependent activity, as well as pharmacological advantages due to the presence of d-amino acids, make them potential candidates for the treatment of mycoses in organs, under various pH environments, especially in cases where the bacterial flora should not be harmed.

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