title: Inhibition of Bacillus anthracis metallo-β-lactamase by compounds with hydroxamic acid functionality.
abstract: Metallo-β-lactamases (MBLs) that catalyze hydrolysis of β-lactam antibiotics are an emerging threat due to their rapid spread. A strain of the bacterium Bacillus anthracis has its ability to produce and secrete a MBL, referred to Bla2. To address this challenge, novel hydroxamic acid-containing compounds such as 3-(heptyloxy)-N-hydroxybenzamide (compound 4) and N-hydroxy-3-((6-(hydroxyamino)-6-oxohexyl)oxy)benzamide (compound 7) were synthesized. Kinetic analysis of microbial inhibition indicated that the both sides of hydroxamic acids containing compound 7 revealed a reversible, competitive inhibition with a Kivalue of 0.18 ± 0.06 μM. The result has reflected that the both sides of dihydroxamic acids in a molecule play a crucial role in the binding affinity rather than monohydroxamic containing compound 4 which was unable to inhibit Bla2. In addition, in silico analysis suggested that compound 7 was coordinated with a zinc ion in the active site of enzyme. These observations suggest that the dihydroxamic acid-containing compound may be a promising drug candidate, and a further implication for designing new inhibitors of Bla2.
authors.affiliation: a Department of Natural Sciences , Northeastern State University , Tahlequah , OK , USA.
authors.forename: Sung-Kun
authors.initials: SK
authors.lastname: Kim
authors.affiliation: a Department of Natural Sciences , Northeastern State University , Tahlequah , OK , USA.
authors.forename: Mara
authors.initials: M
authors.lastname: Demuth
authors.affiliation: b Department of Chemistry and Biochemistry and The Institute of Biomedical Studies , Baylor University , Waco , TX , USA.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Schlesinger
authors.affiliation: b Department of Chemistry and Biochemistry and The Institute of Biomedical Studies , Baylor University , Waco , TX , USA.
authors.forename: Sung Joon
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: c Department Chemistry and Biochemistry , McMurry University , Abilene , TX , USA , and.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Urbanczyk
authors.affiliation: d Department of Chemistry and Biochemistry , Texas Tech University , Lubbock , TX , USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shaw
authors.affiliation: c Department Chemistry and Biochemistry , McMurry University , Abilene , TX , USA , and.
authors.forename: Hyunshun
authors.initials: H
authors.lastname: Shin
mesh_terms: D001408:Bacillus anthracis / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D006877:Hydroxamic Acids; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
keywords: Enzyme kinetics; inhibition; lactamase