Structural Determinants of Inhibitor Selectivity in Prokaryotic IMP Dehydrogenases

The protozoan parasite Cryptosporidium parvum is a major cause of gastrointestinal disease, no effective drug therapy exists to treat this infection Curiously, C parvum IMPDH (CpIMPDH) is most closely related to prokaryotic IMPDHs, suggesting that the parasite obtained its IMPDH gene via horizontal transfer We previously identified inhibitors of CpIMPDH that do not inhibit human IMPDHs Here, we show that these compounds also inhibit IMPDHs from Hehcobacter pylon, Borrelia burgdorferi, and Streptococcus pyogenes, but not from Escherichia coli Residues Ala165 and Tyr358 comprise a structural motif that defines susceptible enzymes Importantly, a second-generation CpIMPDH inhibitor has bacteriocidal activity on H pylon but not E coli We propose that CpIMPDH-targeted inhibitors can be developed into a new class of antibiotics that will spare some commensal bacteria