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Updated: May 14, 2025
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Published on: August 11, 2018
Structure-Activity Study of the Antimicrobial Lipopeptide Humimycin A and Screening Against Multidrug-Resistant
Md Ramim Tanver Rahman1,2,3,4, Louis-David Guay1,2,3,4, Ismail Fliss3,4,5
1Faculty of Pharmacy, Université Laval, Québec, QC G1V 0A6, Canada.
Background:
The emergence of multidrug-resistant (MDR) Staphylococcus aureus presents a critical global health challenge due to treatment failures and high mortality rates. Faced with this growing threat, new antimicrobials with original modes of action are urgently needed, and antimicrobial peptides proved to be promising alternatives.
Objectives:
The aim of this study is to explore the structure-function relationship of the lipopeptide humimycin A, compare the spectrum of activity of the synthetic analogs against a panel of S. aureus isolates, and investigate their binding to the humimycin target, the lipid II flippase MurJ.
Methods:
Humimycin A and 15 analogs were produced by solid-phase peptide synthesis, and their antimicrobial activity was evaluated by agar diffusion and microtitration assays against 19 S. aureus isolates from bovine mastitis and other pathogens.
Results:
Among the synthesized peptides, four humimycin analogs exhibited activity against methicillin-sensitive and methicillin-resistant S. aureus, as well as several isolates in the panel, including MDR S. aureus, with minimal inhibitory concentration values ranging from 0.5 to 256 µg/mL. Results from the structure-activity relationship study showed that the β-hydroxymyristoyl lipid chain and C-terminal carboxylic acid are essential for antimicrobial efficacy. In presence of human erythrocytes, the active humimycin analogs exhibited moderate hemolytic activity, suggesting selectivity indexes ranging from 3 to 27 against the more sensitive S. aureus strains. Critical micelle concentration measurements elucidated micelle formation and proved to not be essential for the antibacterial activity. Molecular docking and 100 ns simulations with the lipid II flippase MurJ (PDB: 5T77) provided favorable binding energy.
Conclusions:
The findings underscore the potential of humimycin analogs as antimicrobials for preventing and treating MDR S. aureus infections in veterinary, animal husbandry, and human medicine.
