Characterization and Inhibition of 1-Deoxy- d -Xylulose 5-Phosphate Reductoisomerase: A Promising Drug Target in Acinetobacter baumannii and Klebsiella pneumoniae

Ball, Haley S.; Girma, Misgina B.; Zainab, Mosufa; Soojhawon, Iswarduth; Couch, Robin D.; Noble, Schroeder M.

doi:10.1021/acsinfecdis.1c00132

Title: Characterization and Inhibition of 1-Deoxy- d -Xylulose 5-Phosphate Reductoisomerase: A Promising Drug Target in Acinetobacter baumannii and Klebsiella pneumoniae

Journal Article · Thu Oct 21 00:00:00 EDT 2021 · ACS Infectious Diseases

DOI:https://doi.org/10.1021/acsinfecdis.1c00132· OSTI ID:1826845

^[1];

^[2]; Zainab, Mosufa ^[2]; Soojhawon, Iswarduth ^[3]; Couch, Robin D. ^[2]; Noble, Schroeder M. ^[3]

Department of Chemistry and Biochemistry, George Mason University, Manassas, Virginia 20109, United States of America, Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Springs, Maryland 20910, United States of America
Department of Chemistry and Biochemistry, George Mason University, Manassas, Virginia 20109, United States of America
Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Springs, Maryland 20910, United States of America

The ESKAPE pathogens comprise a group of multidrug-resistant bacteria that are the leading cause of nosocomial infections worldwide. The prevalence of antibiotic resistant strains and the relative ease by which bacteria acquire resistance genes highlight the continual need for the development of novel antibiotics against new drug targets. The methylerythritol phosphate (MEP) pathway is an attractive target for the development of new antibiotics. The MEP pathway governs the synthesis of isoprenoids, which are key lipid precursors for vital cell components such as ubiquinone and bacterial hopanoids. Additionally, the MEP pathway is entirely distinct from the corresponding mammalian pathway, the mevalonic acid (MVA) pathway, making the first committed enzyme of the MEP pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (IspC), an attractive target for antibiotic development. To facilitate drug development against two of the ESKAPE pathogens, Acinetobacter baumannii and Klebsiella pneumoniae, we cloned, expressed, purified, and characterized IspC from these two Gram-negative bacteria. Enzyme inhibition assays using IspC from these two pathogens, and compounds fosmidomycin and FR900098, indicate IC₅₀ values ranging from 19.5-45.5 nM. Antimicrobial susceptibility tests with these inhibitors reveal that A. baumannii is susceptible to FR900098, whereas K. pneumoniae is susceptible to both compounds. Finally, to facilitate structure-based drug design of inhibitors targeting A. baumannii IspC, we determined the 2.5 Å crystal structure of IspC from A. baumannii in complex with inhibitor FR900098, and cofactors NADPH and magnesium.

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Research Organization:: Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC); US Army Medical Research and Development Command (USAMRDC); Military Infectious Disease Research Program; National Institutes of Health (NIH)

Grant/Contract Number:: SC0014664; W81XWH-17-C-0066; W0161_15_WR; 5R01AI123433-04; HHSN272201700059C

OSTI ID:: 1826845

Alternate ID(s):: OSTI ID: 1904999

Journal Information:: ACS Infectious Diseases, Journal Name: ACS Infectious Diseases Vol. 7 Journal Issue: 11; ISSN 2373-8227

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
drug discovery
antibiotics
multidrug-resistance
bacteria
Acinetobacter baumannii
Klebsiella pneumoniae

Title: Characterization and Inhibition of 1-Deoxy- d -Xylulose 5-Phosphate Reductoisomerase: A Promising Drug Target in Acinetobacter baumannii and Klebsiella pneumoniae

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