The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study

Abstract

Antimicrobial resistance is one of the greatest threats to the global health system. It is imperative that new anti-infective therapeutics be developed against problematic “superbugs.” The cyclic depsipeptide teixobactin holds much promise as a new class of antibiotics for highly resistant Gram-positive pathogens (e.g., methicillin-resistant Staphylococcus aureus [MRSA]). Understanding its molecular mechanism(s) of action could lead to the design of new compounds with a broader activity spectrum. Here, we describe the first metabolomics study to investigate the killing mechanism(s) of teixobactin against MRSA. Our findings revealed that teixobactin significantly disorganized the bacterial cell envelope, as reflected by a profound perturbation in the bacterial membrane lipids and cell wall biosynthesis (peptidoglycan and teichoic acid). Importantly, teixobactin significantly suppressed the main intermediate d -alanyl- d -lactate involved in the mechanism of vancomycin resistance in S. aureus . These novel results help explain the unique mechanism of action of teixobactin and its lack of cross-resistance with vancomycin.