A new bactericidal thiourea antibiotic against drug-resistant Staphylococcus aureus with in vivo activity and no detectable resistance.

The increasing prevalence of drug-resistant Staphylococcus aureus infections highlights the urgent need for innovative treatments. In this study, we present MCZ-038, a bactericidal thiourea derivative from a targeted chemical optimization campaign. MCZ-038 showed potent antimicrobial activity against multidrug-resistant clinical strains of S. aureus and Enterococcus faecium, including methicillin-resistant S. aureus (MRSA), vancomycin-resistant S. aureus (VRSA) and vancomycin-resistant Enterococcus faecium (VRE) with a minimal inhibitory concentration (MIC) of 4-8 μg/mL. MCZ-038 exhibited concentration-dependent bactericidal kill kinetics against S. aureus and synergized with gentamicin, enhancing its potential for combination therapies. Importantly, MCZ-038 demonstrated superior efficacy against biofilms and intracellular bacteria residing in macrophages as compared to FDA approved antibiotics. Furthermore, prolonged exposure of S. aureus to MCZ-038 did not lead to detectable resistance, underscoring its potential as a durable therapeutic option. MCZ-038 targeted membrane fluidity, an unconventional target, which explains lack of generated resistance. In a murine thigh and skin infection model with MDR MRSA NRS119, MCZ-038 effectively reduced bacterial load both alone and in combination with gentamicin. These findings position MCZ-038 as a promising candidate for further optimization of the current liabilities such as metabolic stability and in vitro cytotoxicity and further development against challenging, drug-resistant S. aureus infections.