Antibacterial Activity of MC‐170, a 2,2‐Disubstituted Indole‐3‐one Derivative, Against Staphylococcus aureus via Phosphatidylglycerol

ABSTRACT Staphylococcus aureus , a major human pathogen, poses a significant threat in both healthcare settings and the community. Developing novel inhibitors against S. aureus and elucidating their antibacterial mechanisms represents a highly promising strategy for combating S. aureus infections. In this study, we investigated the molecular mechanism underlying the antibacterial activity of MC170, a 2,2‐disubstituted indole‐3‐one derivative exhibiting potent and selective activity against S. aureus , including methicillin‐resistant S. aureus (MRSA). MC170 demonstrated strong inhibitory effects, with minimum inhibitory concentrations of 1 µg/mL against S. aureus and 2 µg/mL against MRSA. Growth curve measurements and time‐kill curves were employed to analyze the growth patterns of S. aureus exposed to MC170. Transcriptome analysis was performed on S. aureus to further elucidate the mechanism by which MC‐170 inhibits the growth of S. aureus . Transcriptome analysis revealed that MC170 significantly disrupted glycolysis/gluconeogenesis and carbon metabolism. These pathways are critical for generating essential precursors required for bacterial membrane phospholipid biosynthesis. Notably, exogenous phosphatidylglycerol (PG) significantly attenuated the antibacterial activity of MC170. These findings collectively suggest that MC170 exerts its antibacterial effects through inhibition of PG metabolism. Elucidating the antibacterial mechanism of MC170 could provide a foundation for developing novel strategies to combat antimicrobial resistance.