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

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

doi:10.1021/acsinfecdis.1c00342

Journal article

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

Gyan Modi, Gary M Marqus, Mohana Rao Vippila, Deviprasad R Gollapalli, Youngchang Kim, Adhar C Manna, Shibin Chacko, Natalia Maltseva, Xingyou Wang, Ryan T Cullinane, …

ACS infectious diseases, Vol.7(11), pp.3062-3076

09/30/2021

DOI: https://doi.org/10.1021/acsinfecdis.1c00342

PMID: 34590817

Abstract

Virulence

IMP Dehydrogenase

Staphylococcal Infections

Staphylococcus aureus infections

Infectious Diseases

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. 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.

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Title: The Enzymatic Activity of Inosine 5′-Monophosphate Dehydrogenase May Not Be a Vulnerable Target for Staphylococcus aureus Infections
Creators: Gyan Modi - Department of Biology, Brandeis University, Waltham, Massachusetts 02453, United States
Gary M Marqus - Graduate Program in Chemistry, Brandeis University, Waltham Massachusetts 02453, United States
Mohana Rao Vippila - Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Health Building 2, 4849 Calhoun Rd., Houston, Texas 77204, United States
Deviprasad R Gollapalli - Department of Biology, Brandeis University, Waltham, Massachusetts 02453, United States
Youngchang Kim - Center for Structural Genomics of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, Illinois 60667, United States, The Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Lemont, Illinois 60439, United States
Adhar C Manna - Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, United States
Shibin Chacko - Department of Biology, Brandeis University, Waltham, Massachusetts 02453, United States
Natalia Maltseva - Center for Structural Genomics of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, Illinois 60667, United States, The Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Lemont, Illinois 60439, United States
Xingyou Wang - Graduate Program in Chemistry, Brandeis University, Waltham Massachusetts 02453, United States
Ryan T Cullinane - Department of Biochemistry, Brandeis University, Massachusetts 02453, United States
Yubo Zhang - Department of Biochemistry, Brandeis University, Massachusetts 02453, United States
Judy L. M Kotler - Graduate Program in Biochemistry and Biophysics, Brandeis University, Waltham, Massachusetts 02453, United States
Petr Kuzmic - BioKin Ltd., Watertown, Massachusetts 02472, United States
Minjia Zhang - Department of Biology, Brandeis University, Waltham, Massachusetts 02453, United States
Ann P Lawson - Department of Biology, Brandeis University, Waltham, Massachusetts 02453, United States
Andrzej Joachimiak - Center for Structural Genomics of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, Illinois 60667, United States, The Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Lemont, Illinois 60439, United States, Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60367, United States
Ambrose Cheung - Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, United States
Barry B Snider - Department of Chemistry, Brandeis University, Waltham, Massachusetts 02453, United States
David M Rothstein - David Rothstein Consulting, LLC, Lexington, Massachusetts 02421, United States
Gregory D Cuny - Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Health Building 2, 4849 Calhoun Rd., Houston, Texas 77204, United States
Lizbeth Hedstrom - Department of Biology, Brandeis University, Waltham, Massachusetts 02453, United States, Department of Chemistry, Brandeis University, Waltham, Massachusetts 02453, United States
Publication Details: ACS infectious diseases, Vol.7(11), pp.3062-3076
Publisher: American Chemical Society (ACS)
Identifiers: 9924050701001921
Academic Unit: Department of Chemistry; Department of Biology
Language: English
Resource Type: Journal article

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

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