Natural Product BO-1 as an Inner Responsive Molecule Inhibits Antimicrobial-Resistant Staphylococcus aureus via Synergism

Abstract

Multidrug-resistant Staphylococcus aureus, a Gram-positive bacterium that causes several difficult-to-treat human infections, is a considerable threat to global healthcare. We hypothesize that there exist inner responsive molecules (IRMs) which can function synergistically with antibiotics to restore the sensitivity of resistant bacteria to existing antibiotics without inducing new antibiotic resistance. An investigation of the extracts of the Chinese medicinal herb Piper betle L. led to the isolation of six benzoate esters, BO-1−BO-6. Among these, BO-1 as a distinct IRM displayed considerable synergism by potentiating antibacterial activity against five antibiotic-resistant S. aureus strains. Mechanistic studies demonstrated that BO-1 acted as a suppressing drug resistance IRM via inhibiting efflux activity. A combination of BO-1 with ciprofloxacin significantly inhibited resistance to this antibiotic and reversed its resistance in the S. aureus strain. Furthermore, BO-1 effectively enhanced the activity of ciprofloxacin against the efflux fluoroquinolone-resistant S. aureus strain SA1199B that caused infection in two animal models and significantly decreased the inflammatory factors IL-6 and C-reactive protein of the infected mice, thereby showing the practice utility of this approach.