Targeting SufC ATPase in Staphylococcus aureus AR465: Insights from an in silico and molecular docking approach

Abstract

Staphylococcus aureus AR465 (S. aureus AR465) is a deadly pathogen that often inherits multidrug resistance, where the antibiotics become ineffective against it. The iron‑sulfur (FeS) cluster assembly pathway has the potential to serve as a new drug target, allowing for the modification of these molecules to be susceptible to oxidative conditions. Our study focuses on the preliminary stage of the FeS pathway inhibition by inhibiting the SufC protein, unlike previous studies that targeted the final stage. SufC has an Adenosine triphosphate (ATP) binding site. The main goal of this study is to inhibit the SufBCD complex of S. aureus AR465 to bind with other subunits to form an FeS cluster. The Sulfur Utilization Factor (SUF) system plays a massive role in the survival of this pathogen by producing electron carrier proteins which possess FeS cofactors. The SufC protein from the SufBCD system was chosen as the main target for the potential inhibitor molecules. SufC is an ATP-binding cassette (ABC) that transfers an FeS cluster to SufA, which then transports it to an apoprotein involved in electron transport processes. In this research, several drugs were selected which can block this particular stage of the FeS cluster formation pathway. The idea was to competitively inhibit the binding of ATP with the help of inhibitors so that it cannot bind to the desired site of SufC. Eventually, the inhibitor molecule blocks the transfer of the FeS cluster to a newly synthesized apo-protein and kills the pathogen.