L007-0069 kills Staphylococcus aureus in high resistant phenotypes by membrane disruption

Staphylococcus aureus, a common gram-positive pathogenic bacterium, s a main cause of hospital infection. The prevalence rate of methicillin-resistant S. aureus (MRSA) has made its treatment difficult in recent decades. Moreover, S. aureus in the highly tolerant format of biofilm or persister often renders infections refractory. Thus, developing new active compounds against resistant S. aureus is urgently needed. In this study, by a high-throughput screening assay, we identified a small molecule, L007-0069, that exhibited strong and effective bactericidal activity against S. aureus and its high resistance patterns, such as biofilms and persisters, with a low probability of inducing resistance. By molecular dynamics and fluorescent probe analysis, mechanistic studies revealed that the bactericidal activity of L007-0069 was mainly mediated by membrane disruption and metabolic disorder induction. Furthermore, L007-0069 showed effective anti-MRSA effects in vivo in both a wound infection model and a peritonitis-sepsis model, with no detectable toxicity observed at the therapeutic dosage. In conclusion, L007-0069 has the potential to become an alternative for the treatment of highly resistant S. aureus-related infections.