Mycobacterial dihydrofolate reductase inhibitors identified using chemogenomic methods and in vitro validation.

Abstract

The lack of success in target-based screening approaches to the discovery of antibacterial agents has led to reemergence of phenotypic screening as a successful approach of identifying bioactive, antibacterial compounds. A challenge though with this route is then to identify the molecular target(s) and mechanism of action of the hits. This target identification, or deorphanization step, is often essential in further optimization and validation studies. Direct experimental identification of the molecular target of a screening hit is often complex, precisely because the properties and specificity of the hit are not yet optimized against that target, and so many false positives are often obtained. An alternative is to use computational, predictive, approaches to hypothesize a mechanism of action, which can then be validated in a more directed and efficient manner. Specifically here we present experimental validation of an in silico prediction from a large-scale screen performed against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. The two potent anti-tubercular compounds studied in this case, belonging to the tetrahydro-1,3,5-triazin-2-amine (THT) family, were predicted and confirmed to be an inhibitor of dihydrofolate reductase (DHFR), a known essential Mtb gene, and already clinically validated as a drug target. Given the large number of similar screening data sets shared amongst the community, this in vitro validation of these target predictions gives weight to computational approaches to establish the mechanism of action (MoA) of novel screening hit.

Publication DOI: https://doi.org/10.1371/journal.pone.0121492
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
Additional Information: © 2015 Mugumbate et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Publication ISSN: 1932-6203
Last Modified: 27 Mar 2024 08:15
Date Deposited: 20 Sep 2019 10:02
Full Text Link: http://europepm ... ct/med/25799414
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PURE Output Type: Article
Published Date: 2015-03-23
Authors: Mugumbate, G
Abrahams, KA
Cox, JA (ORCID Profile 0000-0001-5208-4056)
Papadatos, G
van, Westen G
Lelièvre, J
Calus, ST
Loman, NJ
Ballell, L
Barros, D
Overington, JP
Besra, GS

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