Format

Send to

Choose Destination
ACS Med Chem Lett. 2014 Jun 10;5(8):846-50. doi: 10.1021/ml500203p. eCollection 2014 Aug 14.

Repurposing cryptosporidium inosine 5'-monophosphate dehydrogenase inhibitors as potential antibacterial agents.

Author information

1
Departments of Biology and Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States.
2
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia , Charlottesville, Virginia 22908, United States.
3
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.
4
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston , 549A Science and Research Building 2, Houston, Texas 77204, United States.
5
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.

Erratum in

  • ACS Med Chem Lett. 2014 Oct 9;5(10):1174.

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.

KEYWORDS:

Gram-positive; IMP dehydrogenase; antibacterial; antibiotic; inhibitor

Supplemental Content

Full text links

Icon for American Chemical Society Icon for PubMed Central
Loading ...
Support Center