An optimized antibiotic from rhizobacteria against multidrug-resistant Gram-positive pathogens

The rapid rise of antibiotic resistance and the urgent need for new antibiotics call for the unique skeleton of compounds with different mechanisms of action. Microbial natural products dominate the preferred chemical scaffolds for antibiotic discovery. A plant-microbial antibiotic is an appealing origin yet underexplored due to a dearth of comprehensive studies of antibacterial activity and structural characteristics. In this study, phloroglucinol derived isolated from the plant-root-associated bacterium Pseudomonas fluorescens was modified for structure–activity relationship study. 2,4-diproylphloroglucinol (DPPG) displayed bactericidal activity against a wide range of Gram-positive bacteria including multidrug-resistant pathogens. Interestingly, the bactericidal mechanism study exhibits that DPPG binds to type II NADH dehydrogenases (NDH-2) in the respiratory chain and disrupts the proton-motive force of S. aureus. We validated the efficacy of DPPG in vivo through mice models associated with infection or contamination. Our finding provides a novel antibiotic to treat S. aureus- associated infections and a potential target for antibiotic design and study.