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    The Mycobactin biosynthesis pathway: a prospective therapeutic target in the battle against Tuberculosis

    Shyam, M. and Shilkar, D. and Verma, H. and Dev, A. and Sinha, B. and Brucoli, F. and Bhakta, Sanjib and Jayaprakash, V. (2021) The Mycobactin biosynthesis pathway: a prospective therapeutic target in the battle against Tuberculosis. Journal of Medicinal Chemistry 64 (1), pp. 71-100. ISSN 0022-2623.

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    Abstract

    Tuberculosis (TB), caused by the unique acid-fast pathogen Mycobacterium tuberculosis (Mtb), is a global challenge and requires novel chemotherapeutic agents, mainly due to the alarming rise in drug-resistant clinical cases. To meet this urgent necessity for new antitubercular specific drugs with novel mechanisms of action, the TB research community has been validating novel drug targets within a multitude of metabolic pathways. The mycobactins (siderophore) biosynthesis pathway, utilised by Mtb, is conserved among the members of the genus Mycobacterium. The mycobactin synthetase complex is a group of conditionally essential enzymes, which are expressed only under in iron-stress conditions in the host to maintain essential physiological functions. Mycobactins are salicyl-capped peptides that are synthesised by mycobacteria to sequestrate iron from the host reservoirs. The mycobactins biosynthesis pathway is entirely non-existent in humans, and its unique presence only in the TB-causing pathogen with its in vivo essentiality provides us with several promising endogenous targets for the discovery of novel leads against the disease. In this perspective, we aim to shed light on the mbt-gene cluster (mbtA-mbtN) responsible for mycobactins biosynthesis and describe the strategies employed to design inhibitors of selected enzymes (MbtI, MbtA, MbtM, and PPTase) encoded by this gene pool. MbtA inhibitors are the most elaborately discussed class of siderophore inhibitors among the enzymes involved in mycobactin biogenesis till up to date. After discussing a plethora of information on inhibitors development by targeting MbtA, we have summarised the structure-activity relationships based upon the chemical modifications of the MbtA inhibitor scaffolds. Additionally, a systematic discussion on MbtI, MbtM and PPTase inhibitors also drawn to take the attention of medicinal chemists for the exploration of these drug targets for accelerating the design of newer drug candidates. Moreover, a brief discussion on nonspecific mycobactin biosynthesis inhibitors is offered and the Trojan horse approach, which is based on heterodimeric conjugated antitubercular drug delivery systems, has also been reviewed.

    Metadata

    Item Type: Article
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Sanjib Bhakta
    Date Deposited: 19 Apr 2023 12:38
    Last Modified: 02 Aug 2023 18:20
    URI: https://eprints.bbk.ac.uk/id/eprint/51044

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