Nitroxide functionalized antibiotics are promising eradication agents against Staphylococcus aureus biofilms

Abstract

ABSTRACTTreatment of Staphylococcus aureus biofilm-related infections represents an important medical challenge worldwide, as biofilms, even of drug-susceptible S. aureus strains, are highly refectory to conventional antibiotic therapy. Nitroxides were recently shown to induce dispersal of Gram-negative biofilms in vitro, but their action against Gram-positive bacterial biofilms remains unknown. Here we demonstrate that the biofilm dispersal activity of nitroxides extends to S. aureus, a clinically important Gram-positive pathogen. Co-administration of the nitroxide CTEMPO with ciprofloxacin significantly improved the antibiotic’s biofilm-eradication activity against S. aureus. Moreover, covalently linking the nitroxide to the antibiotic moiety further reduced ciprofloxacin’s minimal biofilm eradication concentration. Microscopy analysis revealed that fluorescent nitroxide-antibiotic hybrids could penetrate S. aureus biofilms and enter into cells localising at the surface and base of the biofilm structure. No toxicity was observed for the nitroxide CTEMPO and the nitroxide-antibiotic hybrids against human cells. Taken together, our results show that nitroxides can mediate dispersal of Gram-positive biofilms and that dual-acting biofilm-eradication antibiotics could provide broad-spectrum therapies for the treatment of biofilm-related infections.