Computational insights into the inhibition of cell division in Staphylococcus aureus: Towards novel therapeutics

Staphylococcus aureus, a gram-positive bacterium, causes infective endocarditis, osteoarticular, skin, and respiratory infections. The emergence of multidrug-resistant strains, particularly Methicillin-resistant Staphylococcus aureus (MRSA), has caused a 21-35 % rise in bloodstream infections, complicating treatment strategies. Filamentous temperature-sensitive protein Z (FtsZ), a critical protein involved in bacterial cell division, forms a Z-ring at the division site, making it a key target for novel antibacterial therapies. In this study, 1165 phytochemicals were screened, and three lead molecules namely, Aromadendrin, Leucopelargonidin, and 7-Deacetoxy-7-oxogedunin were identified based on their favorable physicochemical properties, drug-likeness, and estimated binding affinities (- 11.73 kcal/mol, - 10.77 kcal/mol, and - 10.38 kcal/mol, respectively) against FtsZ. 100 ns Molecular dynamics simulations conducted in triplicates confirmed the stability of the FtsZ-ligand complexes.Binding free energy calculations revealed that IMPHY003535 (Leucopelargonidin) exhibited the most favorable binding free energy (-27.25 kcal/mol), followed by 7-Deacetoxy-7-oxogedunin (-15.31 kcal/mol) and Aromadendrin (-13.38 kcal/mol). Leucopelargonidin emerged as the most promising inhibitor, highlighting its potential as a lead compound for developing antibacterial agents targeting FtsZ. These findings demonstrate the significant role of phytochemicals in combating antibiotic resistance and the importance of further optimization, including in vivo studies, to assess their therapeutic potential, which could provide new treatment avenues to overcome bacterial resistance mechanisms.