A classic antibiotic reimagined: Rationally designed bacitracin variants exhibit potent activity against vancomycin-resistant pathogens

• DOI: 10.1073/pnas.2315310121
• Publication Date: 2024-07-11T17:50:29Z
• Authors: Ned P. Buijs; Halana C. Vlaming; Ioli Kotsogianni; Melina Arts; Joost Willemse; Yunhao Duan; Francesca M. Alex...; Stephen A. Cochrane; Tanja Schneider; Nathaniel I. Martin
• Keywords: Bacitracin; Lipid II

Bacitracin is a macrocyclic peptide antibiotic that widely used as topical treatment for infections caused by gram-positive bacteria. Mechanistically, bacitracin targets bacteria specifically binding to the phospholipid undecaprenyl pyrophosphate (C 55 PP), which plays key role in bacterial lipid II cycle. Recent crystallographic studies have shown when bound C PP, adopts highly ordered amphipathic conformation. In doing so, all hydrophobic side chains align on one face of bacitracin–C PP complex, presumably interacting with cell membrane. These insights led us undertake structure–activity investigations into individual contribution nonpolar amino acids found bacitracin. To achieve this we designed, synthesized, and evaluated series analogues, number were exhibit significantly enhanced antibacterial activity against clinically relevant, drug-resistant pathogens. As natural product, these next-generation bacitracins form stable complexes PP. The thus obtained serve inform design PP-targeting antibiotics, underexploited strategy.