New antibiotics and new antibiotic targets are urgently needed to combat the emergence of drug resistant pathogens. Knockout experiments consistently find that the genes involved in nucleotide biosynthesis are required for microbial infections. In particular, guaB, the gene encoding inosine monophosphate dehydrogenase (IMPDH), has been deemed essential in many pathogens, including two of the most serious threats: Staphylococcus aureus and Mycobacterium tuberculosis. This presentation will describe our efforts to target prokaryotic IMPDHs, which illustrate the perils and promise of target-based antibiotic discovery- surprisingly variable structure-activity relationships, unsuspected salvage pathways and unanticipated alternative targets.

Essential versus vulnerable: Targeting IMP dehydrogenase for antimicrobial therapy

256th National Meeting (2018)

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