Computational approach to design small molecule inhibitors and identify SarA as a potential therapeutic candidate

Staphylococcus aureus is extensively acknowledged as an opportunistic pathogen because of acquisition and rapid spread of resistance to antibiotics. The temporal expression of many virulence genes is controlled by a major regulatory molecule, SarA that binds to the promoter region of target genes. Constitutive activation of the SarA proteins plays a critical role in the biofilm formation and proliferation of S. aureus. The investigation of SarA inhibitors as potential therapeutic agents is based on the fact that the highly conserved winged region participates in DNA binding and activation is expressed in various staphylococcal species. Computer-assisted drug design was employed to generate first specific low molecular weight compounds that interact with SarA and disrupt the quorum-sensing mechanism. Thirteen potential inhibitors of SarA are identified to improve the understanding of SarA biological function and to disclose future strategies for inhibition.