Drug development:the cell wall as a drug target


The complex and essential cell wall of Mycobacterium tuberculosis represents a plethora of new and old drug targets that collectively form an apparent mycobacterial “Achilles’ heel”. The mycolic acids are long-chain α-alkyl-β-hydroxy fatty acids (C70–90), which are unique to mycobacterial species, forming an integral component of the mycolyl–arabinogalactan–peptidoglycan complex. Their apparent uniqueness to the M. tuberculosis complex has rendered components of mycolic acid biosynthesis as powerful drug targets for specific tuberculosis (TB) chemotherapy. Here, I will discuss a contribution to TB drug discovery by deconvolution of the inhibitory mechanisms of a number of antitubercular compounds targeting mycolic acid biosynthesis. I will begin with the early days, elucidating the mode of action of ethionamide [1] and thiolactomycin [2], each targeting two separate components of the fatty acid synthase II (FAS-II) pathway. I will further discuss the recently discovered tetrahydropyrazo[1,5-a]pyrimidine-3-carboxamide compounds [3] which selectively target the essential, catalytically silent M. tuberculosis EchA6, providing a crucial lipid shunt between β-oxidation and FAS-II and supplying lipid precursors for essential mycolate biosynthesis. Finally, I will discuss the recent discovery of the mode of action of the indazole sulfonamides [4], inhibiting M. tuberculosis KasA by, a completely novel inhibitory mechanism.

Publication DOI: https://doi.org/10.1016/j.ijmyco.2016.09.012
Divisions: College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences > Cell & Tissue Biomedical Research
Additional Information: Abstracts from 'The 2nd Asian-African Congress of International Journal of Mycobacteriology, Iran' Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0).
Uncontrolled Keywords: Microbiology (medical),Infectious Diseases
Publication ISSN: 2212-554X
Last Modified: 08 Jan 2024 08:17
Date Deposited: 21 Dec 2016 15:40
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Meeting abstract
Published Date: 2016-12
Published Online Date: 2016-10-18
Accepted Date: 2016-09-03
Submitted Date: 2016-08-30
Authors: Cox, Jonathan A.G. (ORCID Profile 0000-0001-5208-4056)

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