Genome mining-driven discovery of new tridecaptin analogues with enhanced bioactivity. Paenibacillus peoriae strain:JJ21

The escalating prevalence of multidrug-resistant bacteria, coupled with a strong decline in antibiotic discovery and development, presents a serious challenge in effectively addressing the threat posed by these pathogens. In this study, we present the discovery of the novel lipopeptide antibiotics tridecaptin A5 and tridecaptin D, using an extensive global genome-mining strategy. Through bioinformatically guided organic synthesis and comprehensive antibacterial assays, we demonstrate that synthetic analogues Oct-TriA5 and Oct-TriD exhibit unusual bioactivity spectra not commonly associated with tridecaptins. Surprisingly, Oct-TriD is active against Gram-positive Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium with an MIC range of 4 to 8 ug/mL and possesses moderate activity against Gram-negative pathogens. Interestingly, a single amino acid substitution at position 9 from Phe in Oct-TriA1 to Trp in Oct-TriA5 further expanded the antibacterial spectrum of activity to include both Gram-negative and Gram-positive bacteria. Subsequent screening of analogues incorporating substitutions at position 9 resulted in the identification of Oct-His9, a potent congener with reduced hemolytic and cytotoxic properties and exceptional efficacy against Pseudomonas aeruginosa. These findings underscore the promising potential of tridecaptin analogues as viable alternatives in combatting antibiotic-resistant bacterial pathogens.