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 Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID); 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

References (57)

Physiological concentrations of purines and pyrimidines Traut, Thomas W. Molecular and Cellular Biochemistry, Vol. 140, Issue 1 https://doi.org/10.1007/BF00928361	journal	January 1994
Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors Morrison, J. F. Biochimica et Biophysica Acta (BBA) - Enzymology, Vol. 185, Issue 2 https://doi.org/10.1016/0005-2744(69)90420-3	journal	August 1969
N.m.r. studies of d-ribosylamines in solution: Derivatives of primary amines Chavis, Claude; de Gourcy, Chantal; Dumont, Françoise Carbohydrate Research, Vol. 113, Issue 1 https://doi.org/10.1016/0008-6215(83)88214-7	journal	February 1983
The identification of the two crystalline N-phenyl-d-ribosylamines (“ribose anilides”) by n.m.r. spectroscopy Ellis, Gwynn P.; Williams, J. Michael Carbohydrate Research, Vol. 95, Issue 2 https://doi.org/10.1016/S0008-6215(00)85586-X	journal	September 1981
High-performance liquid chromatographic methods for base and nucleoside analysis in extracellular fluids and in cells Simmonds, R. J.; Harkness, R. A. Journal of Chromatography B: Biomedical Sciences and Applications, Vol. 226, Issue 2 https://doi.org/10.1016/S0378-4347(00)86071-5	journal	December 1981
Structure–activity relationship study of selective benzimidazole-based inhibitors of Cryptosporidium parvum IMPDH Kirubakaran, Sivapriya; Gorla, Suresh Kumar; Sharling, Lisa Bioorganic & Medicinal Chemistry Letters, Vol. 22, Issue 5 https://doi.org/10.1016/j.bmcl.2012.01.029	journal	March 2012
Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV Manchester, John I.; Dussault, Daemian D.; Rose, Jonathan A. Bioorganic & Medicinal Chemistry Letters, Vol. 22, Issue 15 https://doi.org/10.1016/j.bmcl.2012.05.128	journal	August 2012
Phthalazinone inhibitors of inosine-5′-monophosphate dehydrogenase from Cryptosporidium parvum Johnson, Corey R.; Gorla, Suresh Kumar; Kavitha, Mandapati Bioorganic & Medicinal Chemistry Letters, Vol. 23, Issue 4 https://doi.org/10.1016/j.bmcl.2012.12.037	journal	February 2013
Carbohydrate-based inducers of cellular stress for targeting cancer cells Ndombera, Fidelis T.; VanHecke, Garrett C.; Nagi, Shima Bioorganic & Medicinal Chemistry Letters, Vol. 26, Issue 5 https://doi.org/10.1016/j.bmcl.2016.01.063	journal	March 2016
IMPDH2 Is an Intracellular Target of the Cyclophilin A and Sanglifehrin A Complex Pua, Khian Hong; Stiles, Dylan T.; Sowa, Mathew E. Cell Reports, Vol. 18, Issue 2 https://doi.org/10.1016/j.celrep.2016.12.030	journal	January 2017
Structural Determinants of Inhibitor Selectivity in Prokaryotic IMP Dehydrogenases Gollapalli, Deviprasad R.; MacPherson, Iain S.; Liechti, George Chemistry & Biology, Vol. 17, Issue 10 https://doi.org/10.1016/j.chembiol.2010.07.014	journal	October 2010
Evolving medicinal chemistry strategies in antibiotic discovery Pawlowski, Andrew C.; Johnson, Jarrod W.; Wright, Gerard D. Current Opinion in Biotechnology, Vol. 42 https://doi.org/10.1016/j.copbio.2016.04.006	journal	December 2016
Synthesis and Structure–Activity relationship of 1-(5-isoquinolinesulfonyl)piperazine analogues as inhibitors of Mycobacterium tuberculosis IMPDH Singh, Vinayak; Pacitto, Angela; Donini, Stefano European Journal of Medicinal Chemistry, Vol. 174 https://doi.org/10.1016/j.ejmech.2019.04.027	journal	July 2019
Mutation of purD and purF genes further attenuates Brucella abortus strain RB51 Truong, Quang Lam; Cho, Youngjae; Barate, Abhijit Kashinath Microbial Pathogenesis, Vol. 79 https://doi.org/10.1016/j.micpath.2014.12.003	journal	February 2015
Fragment-Based Approach to Targeting Inosine-5′-monophosphate Dehydrogenase (IMPDH) from Mycobacterium tuberculosis Trapero, Ana; Pacitto, Angela; Singh, Vinayak Journal of Medicinal Chemistry, Vol. 61, Issue 7 https://doi.org/10.1021/acs.jmedchem.7b01622	journal	March 2018
Expanding Benzoxazole-Based Inosine 5′-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents Chacko, Shibin; Boshoff, Helena I. M.; Singh, Vinayak Journal of Medicinal Chemistry, Vol. 61, Issue 11 https://doi.org/10.1021/acs.jmedchem.7b01839	journal	May 2018
The Inosine Monophosphate Dehydrogenase, GuaB2, Is a Vulnerable New Bactericidal Drug Target for Tuberculosis Singh, Vinayak; Donini, Stefano; Pacitto, Angela ACS Infectious Diseases, Vol. 3, Issue 1 https://doi.org/10.1021/acsinfecdis.6b00102	journal	September 2016
Essential but Not Vulnerable: Indazole Sulfonamides Targeting Inosine Monophosphate Dehydrogenase as Potential Leads against Mycobacterium tuberculosis Park, Yumi; Pacitto, Angela; Bayliss, Tracy ACS Infectious Diseases, Vol. 3, Issue 1 https://doi.org/10.1021/acsinfecdis.6b00103	journal	October 2016
The Bare Essentials of Antibiotic Target Validation Hedstrom, Lizbeth ACS Infectious Diseases, Vol. 3, Issue 1 https://doi.org/10.1021/acsinfecdis.6b00185	journal	November 2016
Bacillus anthracis Inosine 5′-Monophosphate Dehydrogenase in Action: The First Bacterial Series of Structures of Phosphate Ion-, Substrate-, and Product-Bound Complexes Makowska-Grzyska, Magdalena; Kim, Youngchang; Wu, Ruiying Biochemistry, Vol. 51, Issue 31 https://doi.org/10.1021/bi300511w	journal	July 2012
The Structural Basis of Cryptosporidium-Specific IMP Dehydrogenase Inhibitor Selectivity MacPherson, Iain S.; Kirubakaran, Sivapriya; Gorla, Suresh Kumar Journal of the American Chemical Society, Vol. 132, Issue 4 https://doi.org/10.1021/ja909947a	journal	February 2010
Selective and Potent Urea Inhibitors of Cryptosporidium parvum Inosine 5′-Monophosphate Dehydrogenase Gorla, Suresh Kumar; Kavitha, Mandapati; Zhang, Minjia Journal of Medicinal Chemistry, Vol. 55, Issue 17 https://doi.org/10.1021/jm3007917	journal	September 2012
Optimization of Benzoxazole-Based Inhibitors of Cryptosporidium parvum Inosine 5′-Monophosphate Dehydrogenase Gorla, Suresh Kumar; Kavitha, Mandapati; Zhang, Minjia Journal of Medicinal Chemistry, Vol. 56, Issue 10 https://doi.org/10.1021/jm400241j	journal	May 2013
Fragment-to-Hit-to-Lead Discovery of a Novel Pyridylurea Scaffold of ATP Competitive Dual Targeting Type II Topoisomerase Inhibiting Antibacterial Agents Basarab, Gregory S.; Manchester, John I.; Bist, Shanta Journal of Medicinal Chemistry, Vol. 56, Issue 21 https://doi.org/10.1021/jm401208b	journal	October 2013
Synthesis, in Vitro Evaluation and Cocrystal Structure of 4-Oxo-[1]benzopyrano[4,3- c ]pyrazole Cryptosporidium parvum Inosine 5′-Monophosphate Dehydrogenase ( Cp IMPDH) Inhibitors Sun, Zhuming; Khan, Jihan; Makowska-Grzyska, Magdalena Journal of Medicinal Chemistry, Vol. 57, Issue 24 https://doi.org/10.1021/jm501527z	journal	December 2014
Trends and Exceptions of Physical Properties on Antibacterial Activity for Gram-Positive and Gram-Negative Pathogens Brown, Dean G.; May-Dracka, Tricia L.; Gagnon, Moriah M. Journal of Medicinal Chemistry, Vol. 57, Issue 23 https://doi.org/10.1021/jm501552x	journal	November 2014
Physicochemical Properties of Antibacterial Compounds: Implications for Drug Discovery O’Shea, Rosemarie; Moser, Heinz E. Journal of Medicinal Chemistry, Vol. 51, Issue 10 https://doi.org/10.1021/jm700967e	journal	May 2008
Triazole Inhibitors of Cryptosporidium parvum Inosine 5′-Monophosphate Dehydrogenase Maurya, Sushil K.; Gollapalli, Deviprasad R.; Kirubakaran, Shivapriya Journal of Medicinal Chemistry, Vol. 52, Issue 15 https://doi.org/10.1021/jm900410u	journal	August 2009
Repurposing Cryptosporidium Inosine 5′-Monophosphate Dehydrogenase Inhibitors as Potential Antibacterial Agents Mandapati, Kavitha; Gorla, Suresh Kumar; House, Amanda L. ACS Medicinal Chemistry Letters, Vol. 5, Issue 8 https://doi.org/10.1021/ml500203p	journal	June 2014
Mapping the Protein Interaction Network in Methicillin-Resistant Staphylococcus aureus Cherkasov, Artem; Hsing, Michael; Zoraghi, Roya Journal of Proteome Research, Vol. 10, Issue 3 https://doi.org/10.1021/pr100918u	journal	March 2011
Metabolite concentrations, fluxes and free energies imply efficient enzyme usage Park, Junyoung O.; Rubin, Sara A.; Xu, Yi-Fan Nature Chemical Biology, Vol. 12, Issue 7 https://doi.org/10.1038/nchembio.2077	journal	May 2016
General and condition-specific essential functions of Pseudomonas aeruginosa Lee, Samuel A.; Gallagher, Larry A.; Thongdee, Metawee Proceedings of the National Academy of Sciences, Vol. 112, Issue 16 https://doi.org/10.1073/pnas.1422186112	journal	April 2015
The purine biosynthesis regulator PurR moonlights as a virulence regulator in Staphylococcus aureus Sause, William E.; Balasubramanian, Divya; Irnov, Irnov Proceedings of the National Academy of Sciences, Vol. 116, Issue 27 https://doi.org/10.1073/pnas.1904280116	journal	June 2019
A Novel Cofactor-binding Mode in Bacterial IMP Dehydrogenases Explains Inhibitor Selectivity Makowska-Grzyska, Magdalena; Kim, Youngchang; Maltseva, Natalia Journal of Biological Chemistry, Vol. 290, Issue 9 https://doi.org/10.1074/jbc.M114.619767	journal	January 2015
A Regulatory Role of the Bateman Domain of IMP Dehydrogenase in Adenylate Nucleotide Biosynthesis Pimkin, Maxim; Pimkina, Julia; Markham, George D. Journal of Biological Chemistry, Vol. 284, Issue 12 https://doi.org/10.1074/jbc.M808541200	journal	March 2009
FAF-Drugs4: free ADME-tox filtering computations for chemical biology and early stages drug discovery Lagorce, David; Bouslama, Lina; Becot, Jerome Bioinformatics, Vol. 33, Issue 22 https://doi.org/10.1093/bioinformatics/btx491	journal	July 2017
Characterization of Francisella tularensis Schu S4 defined mutants as live-attenuated vaccine candidates Santiago, Araceli E.; Mann, Barbara J.; Qin, Aiping Pathogens and Disease, Vol. 73, Issue 6 https://doi.org/10.1093/femspd/ftv036	journal	May 2015
Identification of novel diphenyl urea inhibitors of Mt-GuaB2 active against Mycobacterium tuberculosis Usha, Veeraraghavan; Gurcha, Sudagar S.; Lovering, Andrew L. Microbiology, Vol. 157, Issue 1 https://doi.org/10.1099/mic.0.042549-0	journal	January 2011
A fine scale phenotype-genotype virulence map of a bacterial pathogen van Opijnen, T.; Camilli, A. Genome Research, Vol. 22, Issue 12 https://doi.org/10.1101/gr.137430.112	journal	July 2012
Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity Kim, Youngchang; Makowska-Grzyska, Magdalena; Gorla, Suresh Kumar Acta Crystallographica Section F Structural Biology Communications, Vol. 71, Issue 5 https://doi.org/10.1107/S2053230X15000187	journal	April 2015
The CBS subdomain of inosine 5′-monophosphate dehydrogenase regulates purine nucleotide turnover: CBS subdomain of IMPDH Pimkin, Maxim; Markham, George D. Molecular Microbiology, Vol. 68, Issue 2 https://doi.org/10.1111/j.1365-2958.2008.06153.x	journal	February 2008
Benzoxazoles, Phthalazinones, and Arylurea-Based Compounds with IMP Dehydrogenase-Independent Antibacterial Activity against Francisella tularensis Gorla, Suresh Kumar; Zhang, Yan; Rabideau, Meaghan M. Antimicrobial Agents and Chemotherapy, Vol. 61, Issue 10 https://doi.org/10.1128/AAC.00939-17	journal	October 2017
Efficacy of Novel Rifamycin Derivatives against Rifamycin-Sensitive and -Resistant Staphylococcus aureus Isolates in Murine Models of Infection Rothstein, David M. ; Farquhar, Ronald S.; Sirokman, Klari Antimicrobial Agents and Chemotherapy, Vol. 50, Issue 11 https://doi.org/10.1128/AAC.01087-05	journal	November 2006
New Vector for Efficient Allelic Replacement in Naturally Nontransformable, Low-GC-Content, Gram-Positive Bacteria Arnaud, Maryvonne; Chastanet, Arnaud; DÃ¯Â¿Â½barbouillÃ¯Â¿Â½, Michel Applied and Environmental Microbiology, Vol. 70, Issue 11 https://doi.org/10.1128/AEM.70.11.6887-6891.2004	journal	November 2004
Genome-Wide Identification of Genes Required for Fitness of Group A Streptococcus in Human Blood Le Breton, Yoann; Mistry, Pragnesh; Valdes, Kayla M. Infection and Immunity, Vol. 81, Issue 3 https://doi.org/10.1128/IAI.00837-12	journal	March 2013
De Novo Guanine Biosynthesis but Not the Riboswitch-Regulated Purine Salvage Pathway Is Required for Staphylococcus aureus Infection In Vivo Kofoed, Eric M.; Yan, Donghong; Katakam, Anand K. Journal of Bacteriology, Vol. 198, Issue 14 https://doi.org/10.1128/JB.00051-16	journal	July 2016
Complete Bypass of Restriction Systems for Major Staphylococcus aureus Lineages Monk, Ian R.; Tree, Jai J.; Howden, Benjamin P. mBio, Vol. 6, Issue 3 https://doi.org/10.1128/mBio.00308-15	journal	May 2015
Genome-Wide Identification of Klebsiella pneumoniae Fitness Genes during Lung Infection Bachman, Michael A.; Breen, Paul; Deornellas, Valerie mBio, Vol. 6, Issue 3 https://doi.org/10.1128/mBio.00775-15	journal	July 2015
Genome-Wide Identification of Acinetobacter baumannii Genes Necessary for Persistence in the Lung Wang, Nengding; Ozer, Egon A.; Mandel, Mark J. mBio, Vol. 5, Issue 3 https://doi.org/10.1128/mBio.01163-14	journal	June 2014
Genes Contributing to Staphylococcus aureus Fitness in Abscess- and Infection-Related Ecologies Valentino, Michael D.; Foulston, Lucy; Sadaka, Ama mBio, Vol. 5, Issue 5 https://doi.org/10.1128/mBio.01729-14	journal	October 2014
Comprehensive Essentiality Analysis of the Mycobacterium tuberculosis Genome via Saturating Transposon Mutagenesis DeJesus, Michael A.; Gerrick, Elias R.; Xu, Weizhen mBio, Vol. 8, Issue 1 https://doi.org/10.1128/mBio.02133-16	journal	January 2017
Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria Richardson†, Anthony R.; Somerville†, Greg A.; Sonenshein†, Abraham L. Microbiology Spectrum, Vol. 3, Issue 3 https://doi.org/10.1128/microbiolspec.MBP-0004-2014	journal	June 2015
Two Classes of Bacterial IMPDHs according to Their Quaternary Structures and Catalytic Properties Alexandre, Thomas; Rayna, Bertrand; Munier-Lehmann, Hélène PLOS ONE, Vol. 10, Issue 2 https://doi.org/10.1371/journal.pone.0116578	journal	February 2015
Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds Makowska-Grzyska, Magdalena; Kim, Youngchang; Gorla, Suresh Kumar PLOS ONE, Vol. 10, Issue 10 https://doi.org/10.1371/journal.pone.0138976	journal	October 2015
High-Resolution Phenotypic Profiling Defines Genes Essential for Mycobacterial Growth and Cholesterol Catabolism Griffin, Jennifer E.; Gawronski, Jeffrey D.; DeJesus, Michael A. PLoS Pathogens, Vol. 7, Issue 9 https://doi.org/10.1371/journal.ppat.1002251	journal	September 2011
Antibiotic resistance threats in the United States, 2019 Cdc, Centers for Disease Control and Prevention https://doi.org/10.15620/cdc:82532	report	January 2019
The Antibiotic Potential of Prokaryotic IMP Dehydrogenase Inhibitors Hedstrom, L.; Liechti, G.; B. Goldberg, J. Current Medicinal Chemistry, Vol. 18, Issue 13 https://doi.org/10.2174/092986711795590129	journal	May 2011

Similar Records

Characteristics and crystal structure of bacterial inosine-5'-monophosphate dehydrogenase.

Journal Article · Thu Dec 31 23:00:00 EST 1998 · Biochemistry · OSTI ID:942430

Structural comparison of chromosomal and exogenous dihydrofolate reductase from Staphylococcus aureus in complex with the potent inhibitor trimethoprim

Journal Article · Thu Sep 02 00:00:00 EDT 2010 · Proteins · OSTI ID:1006143

Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus

Journal Article · Sat Sep 06 00:00:00 EDT 2014 · European Journal of Medicinal Chemistry · OSTI ID:1160044

Related Subjects

60 APPLIED LIFE SCIENCES
IMPDH
antibiotic space
guaB
guanine nucleotide biosynthesis
target vulnerability
virulenc

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

Citation Formats

References (57)

Similar Records

Related Subjects