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Lipid-tail modification of the antimicrobial peptide P7 enhances membrane disruption and antibacterial activity against Klebsiella pneumoniae

biotechnology
microbiology

Abstract

Antimicrobial peptides (AMPs) are short, host-defense peptides with broad-spectrum antibacterial activity and a low propensity for inducing resistance, positioning them as promising alternatives to conventional antibiotics. The α-helical peptide P7 (KIAKRIWKILRR) previously demonstrated potent antibacterial activity against drug-resistant Salmonella enterica serovar Typhimurium with minimal toxicity. However, its efficacy against ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) has not been characterized. In this study, we evaluated P7 and its N-terminal lipidated analogs conjugated with octanoic (C8), pelargonic (C9), and capric (C10) acids against ESKAPE organisms. Lipidation significantly enhanced antibacterial activity, particularly against K. pneumoniae, and promoted α-helical conformations in membrane-mimetic environments. Lipidated peptides also demonstrated increased resistance to pepsin degradation and improved membrane-permeabilizing and depolarizing capabilities. Among the analogs, C8-P7 had the most favorable therapeutic profile, balancing potent antibacterial activity with low cytotoxicity. Flow cytometry and electron microscopy confirmed membrane disruption as the primary mechanism of antibacterial action. Furthermore, additive effects were observed when C8-P7 was combined with gentamicin or ciprofloxacin, as indicated by the fractional inhibitory concentration index. These findings highlighted the potential of lipid-tail engineering to simultaneously enhance the antimicrobial potency, membrane-disruptive capacity, and proteolytic stability of AMPS, thus offering a promising approach for combating the multidrug-resistant K. pneumoniae and other ESKAPE pathogens.
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