The Enzymatic Activity of Inosine 5'-Monophosphate Dehydrogenase May Not Be a Vulnerable Target for Staphylococcus aureus Infections
Abstract
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 bemore »
- Authors:
-
[1];
[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)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID); USDOE Office of Science (SC)
- OSTI Identifier:
- 1854352
- Grant/Contract Number:
- AC02-06CH11357; 1R21AI138048; R01AI125362; HHSN272201700060C
- Resource Type:
- Accepted Manuscript
- Journal Name:
- ACS Infectious Diseases
- Additional Journal Information:
- Journal Volume: 7; Journal Issue: 11; Journal ID: ISSN 2373-8227
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; IMPDH; antibiotic space; guaB; guanine nucleotide biosynthesis; target vulnerability; virulenc
Citation Formats
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., and Hedstrom, Lizbeth. The Enzymatic Activity of Inosine 5'-Monophosphate Dehydrogenase May Not Be a Vulnerable Target for Staphylococcus aureus Infections. United States: N. p., 2021.
Web. doi:10.1021/acsinfecdis.1c00342.
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. The Enzymatic Activity of Inosine 5'-Monophosphate Dehydrogenase May Not Be a Vulnerable Target for Staphylococcus aureus Infections. United States. https://doi.org/10.1021/acsinfecdis.1c00342
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., and Hedstrom, Lizbeth. Thu .
"The Enzymatic Activity of Inosine 5'-Monophosphate Dehydrogenase May Not Be a Vulnerable Target for Staphylococcus aureus Infections". United States. https://doi.org/10.1021/acsinfecdis.1c00342. https://www.osti.gov/servlets/purl/1854352.
@article{osti_1854352,
title = {The Enzymatic Activity of Inosine 5'-Monophosphate Dehydrogenase May Not Be a Vulnerable Target for Staphylococcus aureus Infections},
author = {Modi, Gyan and Marqus, Gary M. and Vippila, Mohana Rao and Gollapalli, Deviprasad R. and Kim, Youngchang and Manna, Adhar C. and Chacko, Shibin and Maltseva, Natalia and Wang, Xingyou and Cullinane, Ryan T. and Zhang, Yubo and Kotler, Judy L. M. and Kuzmic, Petr and Zhang, Minjia and Lawson, Ann P. and Joachimiak, Andrzej and Cheung, Ambrose and Snider, Barry B. and Rothstein, David M. and Cuny, Gregory D. and Hedstrom, Lizbeth},
abstractNote = {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.},
doi = {10.1021/acsinfecdis.1c00342},
journal = {ACS Infectious Diseases},
number = 11,
volume = 7,
place = {United States},
year = {Thu Sep 30 00:00:00 EDT 2021},
month = {Thu Sep 30 00:00:00 EDT 2021}
}
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