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    Identification and characterization of genetic determinants of Isoniazid and Rifampicin resistance in Mycobacterium tuberculosis in Southern India

    Munir, A. and Kumar, N. and Ramalingam, S.B. and Tamilzhalagan, S. and Shanmugam, S.K. and Palaniappan, A.N. and Nair, D. and Priyadarshini, P. and Natarajan, M. and Tripathy, S. and Ranganathan, U.D. and Peacock, S.J. and Parkhill, J. and Blundell, T.L. and Malhotra, Sony (2019) Identification and characterization of genetic determinants of Isoniazid and Rifampicin resistance in Mycobacterium tuberculosis in Southern India. Scientific Reports 9 (1), p. 10283. ISSN 2045-2322.

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    Abstract

    Drug-resistant tuberculosis (TB), one of the leading causes of death worldwide, arises mainly from spontaneous mutations in the genome of Mycobacterium tuberculosis. There is an urgent need to understand the mechanisms by which the mutations confer resistance in order to identify new drug targets and to design new drugs. Previous studies have reported numerous mutations that confer resistance to anti-TB drugs, but there has been little systematic analysis to understand their genetic background and the potential impacts on the drug target stability and/or interactions. Here, we report the analysis of whole-genome sequence data for 98 clinical M. tuberculosis isolates from a city in southern India. The collection was screened for phenotypic resistance and sequenced to mine the genetic mutations conferring resistance to isoniazid and rifampicin. The most frequent mutation among isoniazid and rifampicin isolates was S315T in katG and S450L in rpoB respectively. The impacts of mutations on protein stability, protein-protein interactions and protein-ligand interactions were analysed using both statistical and machine-learning approaches. Drug-resistant mutations were predicted not only to target active sites in an orthosteric manner, but also to act through allosteric mechanisms arising from distant sites, sometimes at the protein-protein interface.

    Metadata

    Item Type: Article
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    SWORD Depositor: Mr Joe Tenant
    Depositing User: Mr Joe Tenant
    Date Deposited: 04 Oct 2019 08:29
    Last Modified: 05 Oct 2019 09:41
    URI: http://eprints.bbk.ac.uk/id/eprint/28621

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