Retro-inversion imparts antimycobacterial specificity to host defense peptides.

ABSTRACT: Antimicrobial host defense peptides are promising alternatives to resistance prone small molecule antibiotics. To overcome the poor physiologic stability of these therapeutic candidates it is common to prepare proteolytically resistant retro-inverso analogues, where sequence backbone direction and amino acid chirality are reversed. However, in many cases, gains in stability are offset by altered assembly propensities and reduced biologic potency. Here, we show that, contrary to the dogma for non-mycobacterial pathogens, retro-inversion of antimycobacterial host defense peptides improves their potency, specificity and host safety; in some cases by more than an order of magnitude. Biophysical assays suggest that altered mycomembrane thermodynamics, instead of improved proteolytic stability,

SUBMITTER: Glossop HD 

PROVIDER: S-EPMC12800093 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature