Repurposing TAK-285 as An Antibacterial Agent against Multidrug-Resistant Staphylococcus aureus by Targeting Cell Membrane

Infections and antimicrobial resistance are becoming serious global public health crises. Multidrug-resistant Staphylococcus aureus (S. aureus) infections necessitate novel antimicrobial development. In this study, we demonstrated TAK-285, a novel dual HER2/EGFR inhibitor, exerted antibacterial activity against 17 clinical methicillin-resistant S. aureus (MRSA) and 15 methicillin sensitive S. aureus (MSSA) isolates in vitro, with a minimum inhibitory concentration (MIC) of 13.7 μg/mL. At 1 × MIC, TAK-285 completely inhibited the growth of S. aureus bacterial planktonic cells, and at 2 × MIC, it exhibited a superior inhibitory effect on intracellular S. aureus SA113-GFP compared to linezolid. Moreover, TAK-285 effectively inhibited biofilm formation at sub-MIC, eradicated mature biofilm and eliminated bacteria within biofilms, as confirmed by CLSM. Furthermore, the disruption of cell membrane permeability and potential was found by TAK-285 on S. aureus, suggesting its targeting of cell membrane integrity. Global proteomic analysis demonstrated that TAK-285 disturbed the metabolic processes of S. aureus, interfered with biofilm-related gene expression, and disrupted membrane-associated proteins. Conclusively, we repurposed TAK-285 as an antimicrobial with anti-biofilm properties against S. aureus by targeting cell membrane. This study provided strong evidence for the potential of TAK-285 as a promising antimicrobial agent against S. aureus.