The Enzymatic Activity of Inosine 5'-Monophosphate Dehydrogenase May Not Be a Vulnerable Target for Staphylococcus aureus Infections

Modi, Gyan; Marqus, Gary M.; Vippila, Mohana Rao; Gollapalli, Deviprasad R.; Kim, Youngchang; Manna, Adhar C.; Chacko, Shibin; Maltseva, Natalia; Wang, Xingyou; Cullinane, Ryan T.; Zhang, Yubo; Kotler, Judy L. M.; Kuzmic, Petr; Zhang, Minjia; Lawson, Ann P.; Joachimiak, Andrzej; Cheung, Ambrose; Snider, Barry B.; Rothstein, David M.; Cuny, Gregory D.; Hedstrom, Lizbeth

doi:10.1021/acsinfecdis.1c00342

The Enzymatic Activity of Inosine 5'-Monophosphate Dehydrogenase May Not Be a Vulnerable Target for Staphylococcus aureus Infections

Journal Article · Thu Sep 30 00:00:00 EDT 2021 · ACS Infectious Diseases

DOI:https://doi.org/10.1021/acsinfecdis.1c00342· OSTI ID:1854352

Modi, Gyan ^[1]; Marqus, Gary M. ^[1]; Vippila, Mohana Rao ^[2]; Gollapalli, Deviprasad R. ^[1]; Kim, Youngchang ^[3]; Manna, Adhar C. ^[4]; Chacko, Shibin ^[1]; Maltseva, Natalia ^[3]; Wang, Xingyou ^[1]; Cullinane, Ryan T. ^[1]; Zhang, Yubo ^[1]; Kotler, Judy L. M. ^[1]; Kuzmic, Petr ^[5]; Zhang, Minjia ^[1]; Lawson, Ann P. ^[1]; Joachimiak, Andrzej ^[3]; Cheung, Ambrose ^[4]; ^[1]; Rothstein, David M. ^[6]; ^[2] more »

Brandeis Univ., Waltham, MA (United States)
Univ. of Houston, TX (United States)
Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Lemont, IL (United States)
Dartmouth College, Hanover, NH (United States). Geisel School of Medicine
BioKin Ltd., Watertown, MA (United States)
David Rothstein Consulting, LLC, Lexington, MA (United States)

Many bacterial pathogens, including Staphylococcus aureus, 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 S. aureus IMPDH (SaIMPDH) 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. In this work, five compounds failed to display activity in mouse models of septicemia and abscess infection. Inhibitor-resistant S. aureus strains readily emerged in vitro. Resistance resulted from substitutions in the cofactor/inhibitor binding site of SaIMPDH, confirming on-target antibacterial activity. These mutations decreased the binding of all inhibitors tested, but also decreased catalytic activity. Nonetheless, the resistant strains had comparable virulence to wild-type bacteria. Surprisingly, strains expressing catalytically inactive SaIMPDH displayed only a mild virulence defect. Collectively these observations question the vulnerability of the enzymatic activity of SaIMPDH as a target for the treatment of S. aureus infections, suggesting other functions of this protein may be responsible for its role in infection.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1854352

Journal Information:: ACS Infectious Diseases, Journal Name: ACS Infectious Diseases Journal Issue: 11 Vol. 7; ISSN 2373-8227

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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