Structure-based computational investigation of potential TarA inhibitors in Staphylococcus aureus

Staphylococcus aureus, a spherical Gram-positive bacterium commonly found to coinhabit humans, can also cause minor skin infections to life-threatening conditions such as pneumonia in individuals with weakened immune systems. The bacterium has developed resistance against conventional antibiotics. This underscores the urgent need for novel therapeutic strategies that act on the cell structure and therefore integrity of the bacterium. Wall teichoic acids (WTAs) are essential anionic glycopolymers covalently anchored to the peptidoglycan layer of Gram-positive bacteria, including S. aureus and are crucial for bacterial survival. The biosynthesis of WTA occurs by a multi-step process in the cytoplasm and proceeds through membrane translocation and incorporation into the cell wall. The earliest and most essential step in this pathway is catalyzed by TarA, which transfers N-acetylglucosamine (GlcNAc) to undecaprenyl phosphate, forming the WTA precursor lipid I. TarA catalyzes the reaction that serves as the first committed step in WTA biosynthesis, without which the entire WTA polymer cannot be constructed or transported. The TarA protein domain has emerged as a promising target for drug development due to its pivotal role in cell wall biosynthesis. We obtained the S. aureus TarA three-dimensional structure from AlphaFold2, performed virtual screening on diverse compound libraries so as to establish their binding to the target protein, which led to the identification of hit compounds with good binding affinity towards TarA domain and involvement of key amino acid residue interactions. This was followed by molecular docking studies, assessment of drug likeness properties of hit compounds and molecular dynamics (MD) simulations of S. aureus TarA-hit molecule complexes using Amber18 bio-simulations package. MD trajectory analysis; root mean square deviation, root mean square fluctuation, hydrogen bonding analysis, solvent accessible surface area, principal component analysis, secondary structure analysis, clustering analysis, free energy landscape, interactive hydrogen bond matrix, binding free energies of the simulated complexes and steered MD simulations were studied. This study resulted in the identification of new hit molecules with a potential to reduce the risk of the S. aureus infections.