Speaker
Description
The COVID-19 pandemic has set back progress made on antimicrobial resistance (AMR). Without urgent re-focus, we risk slowing down drug discovery and providing treatment for drug resistant Mycobacterium tuberculosis. It is vital to develop new antibiotics with novel mechanism(s) of action to combat different physiological states of TB-causing bacilli. The bacterial cell-wall is a proven target with vast macromolecular machinery, providing several candidate novel therapeutic targets. Our research group has characterised ATP-dependent Mur ligases and Mur ligases like proteins, which forms part of gene clusters and involved in the metabolism of cell-wall peptidoglycan, an essential component of the mycobacterial cell-wall which in turn plays a pivotal role in pathogenicity and establishing host-cell infection. This class of enzymes were found essential, conserved and druggable in all pathogenic mycobacteria and are also responsible for the high drug tolerance often observed to cell-wall acting antibiotics. The key focus of the lecture will be on elucidating structure, function, regulation, and inhibition of these crucial enzyme network in order to validate them as novel therapeutic targets for accelerating new anti-tubercular drug design and discovery.
The lecture will highlight how our collaborative research has integrated high-throughput enzymatic and whole-cell phenotypic assays for screening biological properties of natural or synthetic chemical inhibitors of mycobacterial morphology, growth and viability in vitro as well as in a mycobacteria-infected macrophage model mimicking the intracellular host-environment.
Recent publications by Speaker
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Characterization of the MurT/GatD complex in Mycobacterium tuberculosis towards validating a novel anti-tubercular drug target.(2021) Maitra A, Nukala S, Dickman R, Martin LT, Munshi T, Gupta A, Shepherd AJ, Arnvig KB, Tabor AB, Keep NH, Bhakta S.* JAC (AMR)16;3(1):dlab028. https://doi.org/10.1093/jacamr/dlab028.
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Cell wall peptidoglycan in Mycobacterium tuberculosis: An Achilles' heel for the TB-causing pathogen. Maitra A, Munshi T, Healy J, Martin LT, Vollmer W, Keep NH, Bhakta S.* FEMS Microbiol Rev. (2019);43(5):548-575. https://doi.org/10.1093/femsre/fuz016
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Analogues of Disulfides from Allium stipitatum Demonstrate Potent Anti-tubercular Activities through Drug Efflux Pump and Biofilm Inhibition. (2018) Danquah CA, Kakagianni E, Khondkar P, Maitra A, Rahman M, Evangelopoulos D, McHugh TD, Stapleton P, Malkinson J, Bhakta S, Gibbons S. Sci Rep. 18;8(1):1150. https://doi.org/10.1038/s41598-017-18948-w
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HT-SPOTi: A Rapid Drug Susceptibility Test (DST) to Evaluate Antibiotic Resistance Profiles and Novel Chemicals for Anti-Infective Drug Discovery. Danquah CA, Maitra A, Gibbons S, Faull J, Bhakta S*. Curr Protoc Microbiol. 2016 Feb 8;40:17.8.1-12. https://doi.org/10.1002/9780471729259.mc1708s40
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Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase. Guzman JD, Pesnot T, Barrera DA, Davies HM, McMahon E, Evangelopoulos D, Mortazavi PN, Munshi T, Maitra A, Lamming ED, Angell R, Gershater MC, Redmond JM, Needham D, Ward JM, Cuca LE, Hailes HC, Bhakta S.* J Antimicrob Chemo. 2015;70(6):1691-703. https://doi.org/10.1093/jac/dkv010
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Characterisation of ATP-dependent Mur ligases involved in the biogenesis of cell wall peptidoglycan in Mycobacterium tuberculosis. Munshi T, Gupta A, Evangelopoulos D, Guzman JD, Gibbons S, Keep NH, Bhakta S.* PLoS One. 2013;8(3):e60143. https://doi.org/10.1371/journal.pone.0060143