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Integrated target-based and phenotypic screening approaches for the identification of anti-tubercular agents that bind to the mycobacterial adenylating enzyme MbtA

Ferguson, L; Wells, G; Bhakta, S; Johnson, J; Guzman, J; Parish, T; Prentice, RA; (2019) Integrated target-based and phenotypic screening approaches for the identification of anti-tubercular agents that bind to the mycobacterial adenylating enzyme MbtA. ChemMedChem , 14 (19) pp. 1735-1741. 10.1002/cmdc.201900217. Green open access

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Abstract

Iron is essential for the pathogenicity and virulence of Mycobacterium tuberculosis, which synthesises salicyl‐capped siderophores (mycobactins) to acquire this element from the host. MbtA is the adenylating enzyme that catalyses the initial reaction of mycobactins’ biosynthesis and is solely expressed by mycobacteria. A 3,200‐member library comprised of lead‐like, structurally‐diverse compounds was screened against M. tuberculosis for whole‐cell inhibitory activity. A set of 846 compounds that inhibited the tubercle bacilli growth were then tested for their ability to bind to MbtA using a fluorescence‐based thermal shift assay and NMR‐based Water‐LOGSY and Saturation Transfer Difference (STD) experiments. We identified an attractive hit‐molecule, 5‐hydroxy‐indol‐3‐ethylamino‐(2‐nitro‐4‐trifluoromethyl)benzene (5), that bound with high affinity to MbtA and produced a MIC90 of 13 µM. The ligand was docked into the MbtA crystal structure and displayed an excellent fit within the MbtA active pocket, adopting a different binding mode to the established MbtA inhibitor Sal‐AMS.

Type: Article
Title: Integrated target-based and phenotypic screening approaches for the identification of anti-tubercular agents that bind to the mycobacterial adenylating enzyme MbtA
Location: Germany
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/cmdc.201900217
Publisher version: https://doi.org/10.1002/cmdc.201900217
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Fluorescent-based Thermal Shift Assay, NMR Water-LOGSY, Phenotypic and target-based tuberculosis drug discovery, Saturation Transfer Difference, mycobactins/siderophores
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10081362
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