Rapid Bactericidal Activity of SC5005 Combined with Docosahexaenoic Acid against Multidrug-Resistant Staphylococcus aureus Persisters and Biofilms

Staphylococcus aureus can form persister cells and biofilms, making the treatment difficult and often leading to recurrent infections. In an effort to discover new anti-staphylococcal agents, we observed that oleic acid enhances the activity of a new antibacterial agent, SC5005, against S. aureus and MRSA strains. Subsequent studies showed that saturated or trans-form unsaturated fatty acids did not potentiate SC5005's antibacterial activity. SC5005 only exhibits synergistic bactericidal activity with cis-form unsaturated fatty acids with 16 to 22 carbon atoms. In particular, docosahexaenoic acid (DHA) could reduce the MIC of SC5005 to the subng/mL range against different MRSA strains, including those resistant to second- and third-line antibiotics. However, we did not detect any significant shift in SC5005's cytotoxicity toward four different mammalian cell lines, suggesting that the synergy of DHA and SC5005 is highly selective. Most importantly, this combination demonstrated fast-killing activity, completely eradicating MRSA USA300 planktonic and persister cells within 10 and 30 min, respectively, and removing nearly 98% of MRSA biofilms within 1 min. Together, our findings suggest that the combination of SC5005 and DHA has great potential as a new therapeutic for the treatment of infections caused by multidrug-resistant (MDR) S. aureus biofilms.