Imidazole antibiotics inhibit the nitric oxide dioxygenase function of microbial flavohemoglobin. Antimicrob Agents Chemother 2005 May;49(5):1837-43
Date
04/28/2005Pubmed ID
15855504Pubmed Central ID
PMC1087630DOI
10.1128/AAC.49.5.1837-1843.2005Scopus ID
2-s2.0-18244362036 (requires institutional sign-in at Scopus site) 95 CitationsAbstract
Flavohemoglobins metabolize nitric oxide (NO) to nitrate and protect bacteria and fungi from NO-mediated damage, growth inhibition, and killing by NO-releasing immune cells. Antimicrobial imidazoles were tested for their ability to coordinate flavohemoglobin and inhibit its NO dioxygenase (NOD) function. Miconazole, econazole, clotrimazole, and ketoconazole inhibited the NOD activity of Escherichia coli flavohemoglobin with apparent K(i) values of 80, 550, 1,300, and 5,000 nM, respectively. Saccharomyces cerevisiae, Candida albicans, and Alcaligenes eutrophus enzymes exhibited similar sensitivities to imidazoles. Imidazoles coordinated the heme iron atom, impaired ferric heme reduction, produced uncompetitive inhibition with respect to O(2) and NO, and inhibited NO metabolism by yeasts and bacteria. Nevertheless, these imidazoles were not sufficiently selective to fully mimic the NO-dependent growth stasis seen with NOD-deficient mutants. The results demonstrate a mechanism for NOD inhibition by imidazoles and suggest a target for imidazole engineering.
Author List
Helmick RA, Fletcher AE, Gardner AM, Gessner CR, Hvitved AN, Gustin MC, Gardner PRAuthor
Ryan Helmick MD Associate Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Anti-Bacterial AgentsCandida albicans
Dihydropteridine Reductase
Enzyme Inhibitors
Escherichia coli
Escherichia coli Proteins
Flavin-Adenine Dinucleotide
Heme
Hemeproteins
Imidazoles
Kinetics
NAD
NADH, NADPH Oxidoreductases
Nitric Oxide
Oxidation-Reduction
Oxygenases
Plasmids
