Selective antimicrobial activity and mode of action of adepantins, glycine-rich peptide antibiotics based on anuran antimicrobial peptide sequences

Abstract

A challenge when designing membrane-active peptide antibiotics with therapeutic potential is how to ensure a useful antibacterial activity whilst avoiding unacceptable cytotoxicity for host cells. Understanding their mode of interaction with membranes and the reasons underlying their ability to distinguish between bacterial and eukaryotic cytoplasmic cells is crucial for any rational attempt to improve this selectivity. We have approached this problem by analysing natural helical antimicrobial peptides of anuran origin, using a structure-activity database to determine an antimicrobial selectivity index (SI) relating the minimal inhibitory concentration against Escherichia coli to the haemolytic activity (SI=HC(50)/MIC). A parameter that correlated strongly with SI, derived from the lengthwise asymmetry of the peptides' hydrophobicity (sequence moment), was then used in the "Designer" algorithm to propose novel, highly selective peptides. Amongst these are the 'adepantins', peptides rich in glycines and lysines that are highly selective for Gram-negative bacteria, have an exceptionally low haemolytic activity, and are less than 50% homologous to any other natural or synthetic antimicrobial peptide. In particular, they showed a very high SI for E. coli (up to 400) whilst maintaining an antimicrobial activity in the 0.5-4μM range. Experiments with monomeric, dimeric and fluorescently labelled versions of the adepantins, using different bacterial strains, host cells and model membrane systems provided insight into their mechanism of action.

Cationic acrylate oligomers comprising amino acid mimic moieties demonstrate improved antibacterial killing efficiency

“…The selectivity index is used routinely to describe the selectivity of the compound towards a particular bacterium. 37,38 This is obtained by dividing the haemolysis concentration 50 (HC 50 ) value by the MIC value for a given bacterium: these values are shown in Table SI 7.…”

Novel bioactive peptides from enzymatic hydrolysate of Sardinelle ( Sardinella aurita ) muscle proteins hydrolysed by Bacillus subtilis A26 proteases

“…The most hydrophobic peptides are LVHYAGTVDYN and FRPQQPYPQP. Extensive examination of identified peptides in sub-fraction B, revealed that NVLSGGTTMYPG, FRPQQPYPQP, GPRGLPGSPGNIGPAG, and VRNDNSSRFGKF are glycine and/or proline and/or arginine rich peptides, a common characteristic of several AMPs reported in literature (Ilic' et al, 2013;Otvos, 2002;Dong et al, 2012).…”

A 17-mer Membrane-Active MSI-78 Derivative with Improved Selectivity toward Bacterial Cells

“…To mimic the mammalian membrane 1,2-dimyristoyl-sn-glycerophosphocholine (DMPC) was chosen as it is widely used. 22,23 To mimic the bacterial membrane, a mixture of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) at 1:1 molar ratio was chosen as it has been described as one of the most biologically relevant model membranes for studying the S. aureus strain. 24 ■ EXPERIMENTAL SECTION Reagents.…”