Targeting methicillin-susceptible and -resistant Staphylococcus aureus: Design, synthesis, and antibacterial...

Antimicrobial resistance (AMR) poses a significant global health threat, contributing to millions of deaths annually. Natural products, renowned for their structural diversity, evolutionary optimization, and distinct mechanism of action, have emerged as a promising source of antibacterial leads. In this study, we investigated the potential of cycloartane triterpenoids from Dysoxylum binectariferum to combat Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) related infections. A primary screening of 23 semi-synthesized beddomeilactone amide at a concentration of 50 μg/mL led to the identification of two active molecules (3g and 3s) against S. aureus. Further, a dose-dependent broth microdilution assay revealed 3g molecule as the most potent analog, exhibiting MICs of 5.7 μg/mL and 6.3 μg/mL against S. aureus and MRSA, respectively, indicating the critical role of the piperazine moiety in enhancing antibacterial activity. The potent molecule 3g exhibited bactericidal and bacteriostatic effects along with synergistic potential against S. aureus and MRSA, respectively. Also, it was revealed that 3g molecule induces noteworthy morphological changes in bacterial cells, as confirmed through SEM analysis. Furthermore, mechanistic elucidation of the 3g molecule disclosed the membrane targeting action, triggering various cellular responses and exaggerating the cell death process. Overall, strong antibacterial efficacy, synergistic interactions, and mechanistic insights highlight 3g as a promising plant-derived compound and valuable source for the development of novel therapeutic candidate against staphylococcal infections.