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.
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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.
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