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

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Abstract

Staphylococcus aureus (S. aureus) is an opportunistic gram-positive, non-motile, and non-sporulating bacteria that induces pneumonia, a provocative lung infection affecting mainly the terminal bronchioles and the small air sacs known as alveoli. Recently, it has developed antibiotic resistance to the available consortium as per the WHO reports; thereby, novel remedial targets and resilient medications to forestall and cure this illness are desperately needed. Here, using pan-genomics, a total of 1,387 core proteins were identified. Subtractive proteome analyses further identified 12 proteins that are vital for bacteria. One membrane protein (secY) and two cytoplasmic proteins (asd and trpG) were chosen as possible therapeutic targets concerning minimum % host identity, essentiality, and other cutoff values, such as high resistance in the MDR S. aureus. The UniProt AA sequences of the selected targets were modelled and docked against 3 drug-like chemical libraries. The top-ranked compounds i.e., ZINC82049692, ZINC85492658 and 3a of Isosteviol derivative for Aspartate-semialdehyde dehydrogenase (asd); ZINC38222743, ZINC70455378, and 5 m Isosteviol derivative for Anthranilate synthase component II (trpG); and finally, ZINC72292296, ZINC85632684, and 7 m Isosteviol derivative for Protein translocase subunit secY (secY), were further subjected to molecular dynamics studies for thermodynamic stability and energy calculation. Our study proposes 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 the adapted methodology and the predicted results in this work could make major contributions towards novel drug discovery and their targets in S. aureus caused pneumonia.

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Acknowledgements

This project was carried out in a mutual collaboration among the Department of Chemistry, Islamia College Peshawar, KP-Pakistan, and the JRC Genome Research, PCMD-ICCBS, University of Karachi, Sindh-Pakistan. The author would also like to thank the Deanship of Scientific Research at Shaqra University for supporting this work.

Funding

This research project did not receive any funding/grant from public, commercial or non-profit sector/organization/s.

Author information

Author notes

  1. Ayesha Wisal, Nida Saeed, Muhammad Aurongzeb, Muhammad Shafique, Saman Sohail, Waheed Anwar, Zarrin Basharat and Muhammad Irfan have been contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, Islamia College Peshawar, Peshawar-KP, 25000, Pakistan

    Ayesha Wisal, Saman Sohail, Asad Ullah & Syed S. Hassan

  2. Department of Medical Laboratory Technology, Riphah International University Lahore, Lahore, Pakistan

    Nida Saeed

  3. Department of Applied Sciences, FEST, Hamdard University, Karachi, 74600, Pakistan

    Muhammad Aurongzeb

  4. Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, Saudi Arabia

    Muhammad Shafique

  5. Department of Microbiology, Rehman Medical Institute, Peshawar-KP, 25000, Pakistan

    Waheed Anwar

  6. Alpha Genomics Pvt. Ltd, Islamabad, Pakistan

    Zarrin Basharat

  7. JRC Genome Research, International Center for Chemical and Biological Sciences (ICCBS-PCMD), University of Karachi, Karachi, 75270, Pakistan

    Muhammad Irfan & Syed S. Hassan

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Contributions

Conceived and designed the project: AW, AU, SS and SSH. Analyzed the data: SSH, AW, NS, MS, ZB, MI, MA. Wrote the first draft of the manuscript: SSH, AY, SS. Contributed to the writing of the manuscript: WA, AU. Agreed and reviewed the manuscript data and results: AW, NS, SS, WA, AU, MS, SSH. Jointly prepared the arguments and made critical revision: SSH, AU. Approval of the final manuscript version. The final manuscript was reviewed and approved by all authors.

Corresponding authors

Correspondence to Asad Ullah or Syed S. Hassan.

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Communicated by Martine Collart.

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Wisal, A., Saeed, N., Aurongzeb, M. et al. Bridging drug discovery through hierarchical subtractive genomics against asd, trpG, and secY of pneumonia causing MDR Staphylococcus aureus. Mol Genet Genomics 299, 34 (2024). https://doi.org/10.1007/s00438-024-02115-8

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