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

• 成果类型: Article
• 署名作者: Buijs, Ned P.; Vlaming, Halana C.; Kotsogianni, Ioli; Arts, Melina; Willemse, Joost; Duan, Yunhao; Alexander, Francesca M.; Cochrane, Stephen A.; Schneider, Tanja; Martin, Nathaniel I.
• 署名单位: Leiden University; Leiden University - Excl LUMC; University of Bonn; Queens University Belfast
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10231
• DOI: 10.1073/pnas.2315310121
• 发表日期: 2024-07-16
• 关键词: antibacterial mechanism; antimicrobial activity; clostridium-difficile; enterococcus-faecium; complex-formation; lipid-ii; peptidoglycan; biosynthesis; target; binding

摘要

Bacitracin is a macrocyclic peptide antibiotic that is widely used as a topical treatment for infections caused by gram-- positive bacteria. Mechanistically, bacitracin targets bacteria by specifically binding to the phospholipid undecaprenyl pyrophosphate (C55PP), 55 PP), which plays a key role in the bacterial lipid II cycle. Recent crystallographic studies have shown that when bound to C55PP, 55 PP, bacitracin adopts a highly ordered amphipathic conformation. In doing so, all hydrophobic side chains align on one face of the bacitracin-C55PP 55 PP complex, presumably interacting with the bacterial cell membrane. These insights led us to undertake structure-activity investigations into the individual contribution of the nonpolar amino acids found in bacitracin. To achieve this we designed, synthesized, and evaluated a series of bacitracin analogues, a number of which were found to exhibit significantly enhanced antibacterial activity against clinically relevant, drug-- resistant pathogens. As for the natural product, these next-- generation bacitracins were found to form stable complexes with C55PP. 55 PP. The structure-activity insights thus obtained serve to inform the design of C55PP- 55 PP- targeting antibiotics, a key and underexploited antibacterial strategy.