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Novel gramicidin-derived ????-helical antimicrobialpeptides

Lambden, E.; Wallace, M. I.; Ulmschneider, M. B.

2024-07-30 biophysics
10.1101/2023.12.31.573784 bioRxiv
Show abstract

Combating the threat of multidrug resistance bacteria requires many different approaches. Using structural motifs and sequences from existing antibacterial compounds affords a fresh attack against such bacteria, while circumventing inherited resistance against the existing compound. Gramicidin is a 16 amino acid peptide with an alternating O_SCPLOWLC_SCPLOW- and O_SCPLOWDC_SCPLOW-motif with highly bacteriocidal effects in gram-positive membranes. In the membrane it assumes a {beta}-helix form with two peptides aligned by their N-terminal interactions, and only conducts in such a form. Using gramicidin as a basis, this study employs molecular dynamics simulations as an initial design step and evaluates gramicidin-derived candidates based on their backbone hydrogen-bond interactions, capacity for conductance, profile of their RMSD over the course of the simulation, and how the peptide interacts with the phospholipid headgroups. There are twelve candidate systems with results comparable to gramicidin and the factors at play in their efficacy are examined.

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