Rational design of new cyclic analogues of the antimicrobial lipopeptide tridecaptin A1

Abstract

Non-ribosomal peptides (NRPs) are a rich source of antibiotic candidates. However, it was recently discovered that resistance to NRPs can be mediated by D-stereoselective peptidases. The tridecaptins, a class of NRPs that selectively target Gram-negative bacteria, are degraded by the D-peptidase TriF. Through analysis of a solution NMR structure of tridecaptin A₁, we have rationally synthesized new cyclic tridecaptin analogues that retain strong antimicrobial activity and are resistant to TriF.