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Abstract
In contrast with most bacteria, which harbour a single inosine monophosphate dehydrogenase (IMPDH) gene, the genomic sequence of Mycobacterium tuberculosis H37Rv predicts three genes encoding IMPDH: guaB1, guaB2 and guaB3. These three genes were cloned and expressed in Escherichia coli to evaluate functional IMPDH activity. Purified recombinant Mt-GuaB2, which uses inosine monophosphate as a substrate, was identified as the only active GuaB orthologue in M. tuberculosis and showed optimal activity at pH 8.5 and 37 °C. Mt-GuaB2 was inhibited significantly in vitro by a panel of diphenyl urea-based derivatives, which were also potent anti-mycobacterial agents against M. tuberculosis and Mycobacterium smegmatis, with MICs in the range of 0.2-0.5 μg ml(-1). When Mt-GuaB2 was overexpressed on a plasmid in trans in M. smegmatis, a diphenyl urea analogue showed a 16-fold increase in MIC. Interestingly, when Mt-GuaB orthologues (Mt-GuaB1 and 3) were also overexpressed on a plasmid in trans in M. smegmatis, they also conferred resistance, suggesting that although these Mt-GuaB orthologues were inactive in vitro, they presumably titrate the effect of the inhibitory properties of the active compounds in vivo.
Original language | English |
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Pages (from-to) | 290-9 |
Number of pages | 10 |
Journal | Microbiology |
Volume | 157 |
Issue number | Pt 1 |
DOIs | |
Publication status | Published - 1 Jan 2011 |
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Dive into the research topics of 'Identification of novel diphenyl urea inhibitors of Mt-GuaB2 active against Mycobacterium tuberculosis.'. Together they form a unique fingerprint.Projects
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Biochemical characterisation of pivotal enzymes involved in mycobacterial mycolic acid biosynthesis
Besra, D. (Principal Investigator), Bhatt, A. (Co-Investigator) & Futterer, K. (Co-Investigator)
1/06/10 → 31/05/13
Project: Research Councils