title: Repurposing cryptosporidium inosine 5'-monophosphate dehydrogenase inhibitors as potential antibacterial agents.
abstract: Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the pivotal step in guanine nucleotide biosynthesis. IMPDH is a target for immunosuppressive, antiviral, and anticancer drugs, but, as of yet, has not been exploited for antimicrobial therapy. We have previously reported potent inhibitors of IMPDH from the protozoan parasite Cryptosporidium parvum (CpIMPDH). Many pathogenic bacteria, including Bacillus anthracis, Staphylococcus aureus, and Listeria monocytogenes, contain IMPDHs that should also be inhibited by these compounds. Herein, we present the structure-activity relationships for the inhibition of B. anthracis IMPDH (BaIMPDH) and antibacterial activity of 140 compounds from five structurally distinct compound series. Many potent inhibitors of BaIMPDH were identified (78% with IC50 ≤ 1 μM). Four compounds had minimum inhibitory concentrations (MIC) of less than 2 μM against B. anthracis Sterne 770. These compounds also displayed antibacterial activity against S. aureus and L. monocytogenes.
authors.affiliation: Departments of Biology and Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Mandapati
authors.affiliation: Departments of Biology and Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States.
authors.forename: Suresh Kumar
authors.initials: SK
authors.lastname: Gorla
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia , Charlottesville, Virginia 22908, United States.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: House
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia , Charlottesville, Virginia 22908, United States.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: McKenney
authors.affiliation: Departments of Biology and Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States.
authors.forename: Minjia
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Departments of Biology and Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States.
authors.forename: Suraj Nagendra
authors.initials: SN
authors.lastname: Rao
authors.affiliation: Departments of Biology and Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States.
authors.forename: Deviprasad R
authors.initials: DR
authors.lastname: Gollapalli
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia , Charlottesville, Virginia 22908, United States ; Department of Medicine, Division of Infectious Diseases and International Health, University of Virginia , Charlottesville, Virginia 22908, United States.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Mann
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia , Charlottesville, Virginia 22908, United States.
authors.forename: Joanna B
authors.initials: JB
authors.lastname: Goldberg
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston , 549A Science and Research Building 2, Houston, Texas 77204, United States.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia , Charlottesville, Virginia 22908, United States.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Glomski
authors.affiliation: Departments of Biology and Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States ; Departments of Biology and Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States.
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Hedstrom
keywords: Gram-positive; IMP dehydrogenase; antibacterial; antibiotic; inhibitor