1887

Abstract

In contrast with most bacteria, which harbour a single inosine monophosphate dehydrogenase (IMPDH) gene, the genomic sequence of H37Rv predicts three genes encoding IMPDH: , and . These three genes were cloned and expressed in 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 and showed optimal activity at pH 8.5 and 37 °C. Mt-GuaB2 was inhibited significantly by a panel of diphenyl urea-based derivatives, which were also potent anti-mycobacterial agents against and , with MICs in the range of 0.2–0.5 μg ml. When Mt-GuaB2 was overexpressed on a plasmid in , a diphenyl urea analogue showed a 16-fold increase in MIC. Interestingly, when Mt-GuaB orthologues (MtGuaB1 and 3) were also overexpressed on a plasmid in , they also conferred resistance, suggesting that although these Mt-GuaB orthologues were inactive , they presumably titrate the effect of the inhibitory properties of the active compounds .

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2011-01-01
2020-01-28
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