Discovery of Salifungin as a Repurposed Antibiotic against Methicillin-Resistant Staphylococcus aureus with Limited Resistance Development

Exploring novel antimicrobial drugs
and strategies has
become essential
to the fight MRSA-associated infections. Herein, we found that membrane-disrupted
repurposed antibiotic salifungin had excellent bactericidal activity
against MRSA, with limited development of drug resistance. Furthermore,
adding salifungin effectively decreased the minimum inhibitory concentrations
of clinical antibiotics against Staphylococcus aureus. Evaluations of the mechanism demonstrated that salifungin disrupted
the level of H+ and K+ ions using hydrophilic
and lipophilic groups to interact with bacterial membranes, causing
the disruption of bacterial proton motive force followed by impacting
on bacterial the function of the respiratory chain and adenosine 5′-triphosphate,
thereby inhibiting phosphatidic acid biosynthesis. Moreover, salifungin
also significantly inhibited the formation of bacterial biofilms and
eliminated established bacterial biofilms by interfering with bacterial
membrane potential and inhibiting biofilm-associated gene expression,
which was even better than clinical antibiotics. Finally, salifungin
exhibited efficacy comparable to or even better than that of vancomycin
in the MRSA-infected animal models. In conclusion, these results indicate
that salifungin can be a potential drug for treating MRSA-associated
infections.