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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

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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 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:
DateEvent
2011Published
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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