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Identification of novel diphenyl urea inhibitors of Mt-GuaB2 active against Mycobacterium tuberculosis
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Usha, Veeraraghavan, Gurcha, Sudagar S., Lovering, Andrew L., Lloyd, Adrian, Papaemmanouil, A., Reynolds, Robert C. and Besra, Gurdyal S. (2011) Identification of novel diphenyl urea inhibitors of Mt-GuaB2 active against Mycobacterium tuberculosis. Microbiology, Vol.157 (No.1). pp. 290-299. doi:10.1099/mic.0.042549-0 ISSN 1350-0872.
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Official URL: http://dx.doi.org/10.1099/mic.0.042549-0
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 degrees 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 mu g 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.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
| Journal or Publication Title: | Microbiology | ||||
| Publisher: | Society for General Microbiology | ||||
| ISSN: | 1350-0872 | ||||
| Official Date: | 2011 | ||||
| Dates: |
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| Volume: | Vol.157 | ||||
| Number: | No.1 | ||||
| Page Range: | pp. 290-299 | ||||
| DOI: | 10.1099/mic.0.042549-0 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access | ||||
| Funder: | Royal Society , Medical Research Council (MRC) |
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