Discovery and Derivatization of Tridecaptin Antibiotics with Altered Host Specificity and Enhanced Bioactivity

• Published in: ACS chemical biology 2024-05, Vol.19 (5), p.1106-1115
• Main Authors: Machushynets, Nataliia V., Al Ayed, Karol, Terlouw, Barbara R., Du, Chao, Buijs, Ned P., Willemse, Joost, Elsayed, Somayah S., Schill, Julian, Trebosc, Vincent, Pieren, Michel, Alexander, Francesca M., Cochrane, Stephen A., Liles, Mark R., Medema, Marnix H., Martin, Nathaniel I., van Wezel, Gilles P.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Drug Discovery; Host Specificity; Humans; Lipopeptides - chemistry; Lipopeptides - pharmacology; Microbial Sensitivity Tests; Peptides; Pseudomonas aeruginosa - drug effects
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.4c00034

The prevalence of multidrug-resistant (MDR) pathogens combined with a decline in antibiotic discovery presents a major challenge for health care. To refill the discovery pipeline, we need to find new ways to uncover new chemical entities. Here, we report the global genome mining-guided discovery of new lipopeptide antibiotics tridecaptin A5 and tridecaptin D, which exhibit unusual bioactivities within their class. The change in the antibacterial spectrum of Oct-TriA5 was explained solely by a Phe to Trp substitution as compared to Oct-TriA1, while Oct-TriD contained 6 substitutions. Metabolomic analysis of producer Paenibacillus sp. JJ-21 validated the predicted amino acid sequence of tridecaptin A5. Screening of tridecaptin analogues substituted at position 9 identified Oct-His9 as a potent congener with exceptional efficacy against Pseudomonas aeruginosa and reduced hemolytic and cytotoxic properties. Our work highlights the promise of tridecaptin analogues to combat MDR pathogens.