%0 Journal Article %A Usha, Veeraraghavan %A Gurcha, Sudagar S. %A Lovering, Andrew L. %A Lloyd, Adrian J. %A Papaemmanouil, Athina %A Reynolds, Robert C. %A Besra, Gurdyal S. %T Identification of novel diphenyl urea inhibitors of Mt-GuaB2 active against Mycobacterium tuberculosis %D 2011 %J Microbiology, %V 157 %N 1 %P 290-299 %@ 1465-2080 %R https://doi.org/10.1099/mic.0.042549-0 %K XDR, extensively drug resistant %K IMDPH, IMP dehydrogenase %K TB, tuberculosis %K IMP, inosine monophosphate %K XMP, xanthosine monophosphate %K MDR, multi-drug resistant %K DPU, diphenyl urea %K GMP, guanosine monophosphate %I Microbiology Society, %X 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. %U https://www.microbiologyresearch.org/content/journal/micro/10.1099/mic.0.042549-0