biostudies-literatureModi GNational Institute of Allergy and Infectious DiseasesU.S. Department of EnergyNIAID NIH HHSBrandeis University3062-3076https://www.ebi.ac.uk/biostudies/studies/S-EPMC9575405biostudies-literatureUnknown7(11)Many bacterial pathogens, including <i>Staphylococcus aureus</i>, require inosine 5'-monophosphate dehydrogenase (IMPDH) for infection, making this enzyme a promising new target for antibiotics. Although potent selective inhibitors of bacterial IMPDHs have been reported, relatively few have displayed antibacterial activity. Here we use structure-informed design to obtain inhibitors of <i>S. aureus</i> IMPDH (<i>Sa</i>IMPDH) that have potent antibacterial activity (minimal inhibitory concentrations less than 2 μM) and low cytotoxicity in mammalian cells. The physicochemical properties of the most active compounds were within typical Lipinski/Veber space, suggesting that polarity is not a general requirement for achieving antibacterial activity. Five compounds failed to display activity in mACS infectious diseasesThe Enzymatic Activity of Inosine 5'-Monophosphate Dehydrogenase May Not Be a Vulnerable Target for <i>Staphylococcus aureus</i> Infections.PMC9575405DE-AC02-06CH113571R21AI138048Sprout AwardR21 AI138048HHSN272201700060CR01 AI125362R01AI125362Hedstrom LJoachimiak ARothstein DMCullinane RTZhang MLawson APCuny GDMarqus GMManna ACZhang YKuzmic PKim YSnider BBWang XCheung AVippila MRChacko SMaltseva NKotler JLMModi GGollapalli DRfalseThe Enzymatic Activity of Inosine 5'-Monophosphate Dehydrogenase May Not Be a Vulnerable Target for <i>Staphylococcus aureus</i> Infections.Many bacterial pathogens, including <i>Staphylococcus aureus</i>, require inosine 5'-monophosphate dehydrogenase (IMPDH) for infection, making this enzyme a promising new target for antibiotics. Although potent selective inhibitors of bacterial IMPDHs have been reported, relatively few have displayed antibacterial activity. Here we use structure-informed design to obtain inhibitors of <i>S. aureus</i> IMPDH (<i>Sa</i>IMPDH) that have potent antibacterial activity (minimal inhibitory concentrations less than 2 μM) and low cytotoxicity in mammalian cells. The physicochemical properties of the most active compounds were within typical Lipinski/Veber space, suggesting that polarity is not a general requirement for achieving antibacterial activity. Five compounds failed to display activity in m2021-01-01T00:00:00Z2021 Nov2026-05-27T19:09:13.265Z2025-02-19T03:22:53.024ZS-EPMC95754053459081710.1021/acsinfecdis.1c00342