Linear Antimicrobial Peptide, Containing a Diindolyl Methane Unnatural Amino Acid, Potentiates Gentamicin Against Methicillin‐Resistant <i>Staphylococcus aureus</i>

The headway for the management of emerging resistant microbial strains has become a demanding task. Over the years, antimicrobial peptides (AMP), have been recognized and explored for their highly systematized SAR and antibacterial properties. With this background, we have reported a new class of AMPs. These peptides incorporate an unnatural amino acid, with a motivation from cruciferous bioactive phytochemical bisindoles methane derivatives with highly selective antimicrobial action. These peptides may also be considered as linear derivatives of hirsutide isolated from entomopathogenic fungus. The synthesized peptides were tested for their antimicrobial activity against an ESKAPE pathogen panel, where peptide 3 exhibited equipotent MIC and potent synergistic action along with gentamicin against Staphylococcus aureus and Enterococcus clinical isolates. This combination was also able to repotentiate gentamicin against NRS119, a gentamicin-resistant MRSA. Molecular dynamics study and free energy calculations provided insights to membrane disruptive properties of AMP action, which assisted gentamicin pass through the lipid-water interface.