The rising prevalence of multidrug-resistant (MDR) Staphylococcus aureus (S. aureus), particularly methicillin-resistant S. aureus (MRSA), poses ongoing clinical challenges, driving an urgent need for novel antibacterial agents. Here, we report the first identification of BMS-303141 (an ATP-citrate lyase inhibitor) as a potent anti-staphylococcal compound that induces multi-pathway cellular disruption. BMS-303141 exhibited potent antibacterial activity against MRSA, with the minimum inhibitory concentration (MIC) ranging from 6.25 to 12.5 μM (2.65–5.30 μg/mL) and inhibited biofilm formation at sub-MIC concentrations. Integrative proteomics and whole-genome sequencing revealed multi-pathway cellular disruption involving cell wall integrity and protein synthesis pathways, as indicated by differentially expressed proteins and mutated genes (Atl, LytH, Rot, OatA, Asd, ClfA, FnbA, SdrD, dltB). Mechanistic studies further demonstrated disruption of membrane phospholipid homeostasis and peptidoglycan homeostasis by BMS-303141. Critically, in mouse wound and thigh muscle infection models, BMS-303141 significantly reduced bacterial burden and accelerated healing, demonstrating therapeutic potential against S. aureus. Together, these findings indicate that BMS-303141 is a promising lead for developing new antibacterial agents against S. aureus and its resistant strains.
Ma et al. (Mon,) studied this question.