Bridging drug discovery through hierarchical subtractive genomics against asd, trpG, and secY of pneumonia causing MDR Staphylococcus aureus

Abstract

Staphylococcus aureus (S. aureus) is an opportunistic gram-positive, non-motile, and non-sporulating bacteria that induce pneumonia, a provocative lung infection affecting mainly the terminal bronchioles and the small air sacs known as alveoli. Recently, S. aureus has developed resistance to the available antibiotics consortium as per WHO reports, thereby, novel remedial targets and strong medications to forestall and cure this illness are desperately needed.Here, using pangenomics, a total of 1,387 core proteins were identi ed. Subtractive proteome analysis is utilized to further identify 12 proteins that are vital for bacteria. One membrane protein (secY) and two cytoplasmic proteins (asd and trpG) were chosen as possible therapeutic targets with respect to minimum % host identity, essentiality, and other cutoff values such as high resistance in MDR S. aureus. The amino acid sequence of selected targets was modeled and then docked against drug-like chemical libraries. The top-ranked compounds i.e., ZINC82049692, ZINC85492658 and 3a of Isosteviol derivative for Aspartatesemialdehyde dehydrogenase (asd); ZINC38222743, ZINC70455378, and 5m Isosteviol derivative for Anthranilate synthase component II (trpG); and nally, ZINC72292296, ZINC85632684, and 7m Isosteviol derivative for Protein translocase subunit SecY (secY), were further subjected to molecular dynamics studies for thermodynamic stability and validation. In this study, we discovered new therapeutic targets in S. aureus, some of which have previously been reported in other pathogenic microorganisms. Owing to further experimental validation, We anticipate that our method and results will make major contributions in the discovery of novel drugs and their targets in S. aureus-caused pneumonia.