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Development of a one-pot assay for screening and identification of Mur pathway inhibitors in Mycobacterium tuberculosis
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Development of a one-pot assay for screening and identification of Mur pathway inhibitors in Mycobacterium tuberculosis
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Journal Article
Development of a one-pot assay for screening and identification of Mur pathway inhibitors in Mycobacterium tuberculosis
2016
Overview
The cell wall of
Mycobacterium tuberculosis
(Mtb) consists of peptidoglycan, arabinogalactan and mycolic acids. The cytoplasmic steps in the peptidoglycan biosynthetic pathway, catalyzed by the Mur (A-F) enzymes, involve the synthesis of UDP-n-acetylmuramyl pentapeptide, a key precursor molecule required for the formation of the peptidoglycan monomeric building blocks. Mur enzymes are indispensable for cell integrity and their lack of counterparts in eukaryotes suggests them to be promising Mtb drug targets. However, the caveat is that most of the current assays utilize a single Mur enzyme, thereby identifying inhibitors against only one of the enzymes. Here, we report development of a one-pot assay that reconstructs the entire Mtb Mur pathway
in vitro
and has the advantage of eliminating the requirement for nucleotide intermediates in the pathway as substrates. The MurA-MurF enzymes were purified and a one-pot assay was developed through optimization of successive coupled enzyme assays using UDP-n-acetylglucosamine as the initial sugar substrate. The assay is biochemically characterized and optimized for high-throughput screening of molecules that could disrupt multiple targets within the pathway. Furthermore, we have validated the assay by performing it to identify D-Cycloserine and furan-based benzene-derived compounds with known Mur ligase inhibition as inhibitors of Mtb MurE and MurF.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 38/77
/ 82/80
/ 82/83
/ Alkyl and Aryl Transferases - metabolism
/ Bacterial Proteins - metabolism
/ Benzene
/ Enzyme Inhibitors - chemistry
/ Enzyme Inhibitors - pharmacology
/ Enzymes
/ Humanities and Social Sciences
/ Mycobacterium tuberculosis - drug effects
/ Mycobacterium tuberculosis - metabolism
/ Peptide Synthases - metabolism
/ Science
/ Signal Transduction - drug effects
/ Sugar
/ Uridine Diphosphate N-Acetylmuramic Acid - analogs & derivatives
