Please use this identifier to cite or link to this item: https://cris.library.msu.ac.zw//handle/11408/4905
Title: Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen
Authors: Cox, Jonathan A G
Mugumbate, Grace
Peral, Laura Vela-Glez Del
Jankute, Monika
Abrahams, Katherine A
Jervis, Peter
Jackenkroll, Stefan
Perez, Arancha
Alemparte, Carlos
Esquivias, Jorge
Lelièvre, Joël
Ramon, Fernando
Barros, David
Ballell, Lluis
Besra, Gurdyal S
Keywords: Antibiotics
High-throughput screening
Phenotypic screening
Target validation
Issue Date: 2016
Publisher: Nature Research
Series/Report no.: Scientific reports;Vol. 6,No. 38986
Abstract: High-throughput phenotypic screens have re-emerged as screening tools in antibiotic discovery. The advent of such technologies has rapidly accelerated the identification of 'hit' compounds. A pre-requisite to medicinal chemistry optimisation programmes required to improve the drug-like properties of a 'hit' molecule is identification of its mode of action. Herein, we have combined phenotypic screening with a biased target-specific screen. The inosine monophosphate dehydrogenase (IMPDH) protein GuaB2 has been identified as a drugable target in Mycobacterium tuberculosis, however previously identified compounds lack the desired characteristics necessary for further development into lead-like molecules. This study has identified 7 new chemical series from a high-throughput resistance-based phenotypic screen using Mycobacterium bovis BCG over-expressing GuaB2. Hit compounds were identified in a single shot high-throughput screen, validated by dose response and subjected to further biochemical analysis. The compounds were also assessed using molecular docking experiments, providing a platform for their further optimisation using medicinal chemistry. This work demonstrates the versatility and potential of GuaB2 as an anti-tubercular drug target.
URI: https://www.nature.com/articles/srep38986
http://hdl.handle.net/11408/4905
ISSN: 2045-2322
Appears in Collections:Research Papers

Files in This Item:
File Description SizeFormat 
Novel inhibitors. pdf.pdfFull Text.pdf3.36 MBAdobe PDFView/Open
Show full item record

Page view(s)

72
checked on Dec 5, 2024

Download(s)

10
checked on Dec 5, 2024

Google ScholarTM

Check


Items in MSUIR are protected by copyright, with all rights reserved, unless otherwise indicated.