Computational Target-Based Screening of Anti-MRSA Natural Products Reveals Potential Multitarget Mechanisms of Action through Peptidoglycan Synthesis Proteins

[Image: see text] Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of bacterial infections in both healthcare and community settings. MRSA can acquire resistance to any current antibiotic, which has major implications for its current and future treatment options. As such, it is globally a major focus for infection control efforts. The mechanical rigidity provided by peptidoglycans in the bacteria cell walls makes it a promising target for broad-spectrum antibacterial drug discovery. The development of drugs that can target different stages of the synthesis of peptidoglycan in MRSA may compromise the integrity of its cell wall and consequently result in the rapid decline of diseases associated with this drug-resistant bacteria. The present study is aimed at screening natural products with known in vitro activities against MRSA to identify their potential to inhibit the proteins involved in the biosynthesis of the peptidoglycan cell wall. A total of 262 compounds were obtained when a literature survey was conducted on anti-MRSA natural products (AMNPs). Virtual screening of the AMNPs was performed against various proteins (targets) that are involved in the biosynthesis of the peptidoglycan (PPC) cell wall using Schrödinger software (release 2020–3) to determine their binding affinities. Nine AMNPs were identified as potential multitarget inhibitors against peptidoglycan biosynthesis proteins. Among these compounds, DB211 showed the strongest binding affinity and interactions with six protein targets, representing three stages of peptidoglycan biosynthesis, and thus was selected as the most promising compound. The MD simulation results for DB211 and its proteins indicated that the protein-ligand complexes were relatively stable over the simulation period of 100 ns. In conclusion, DB211 showed the potential to inhibit six proteins involved in the biosynthesis of the peptidoglycan cell wall in MRSA, thus reducing the chance of MRSA developing resistance to this compound. Therefore, DB211 provided a starting point for the design of new compounds that can inhibit multiple targets in the biosynthesis of the peptidoglycan layer in MRSA.