title: Evaluation of penicillin-based inhibitors of the class A and B beta-lactamases from Bacillus anthracis.
abstract: Bacillus anthracis contains a class A (Bla1) and class B (Bla2) beta-lactamase, which confer resistance to beta-lactam antibiotics when expressed in Escherichia coli. In an effort to find new beta-lactamase inhibitors, several penicillin derivatives have been evaluated including experimental compounds incorporating a 6-mercaptomethyl group or a 6-pyridylmethylidene group, along with clavulanate and tazobactam, as inhibitors against Bla1 and Bla2. The 6-mercaptomethyl-substituted penicillins showed much greater activity against the zinc-containing Bla2 than Bla1. The compound that incorporated a 6-pyridylmethylidene substituent and a catecholic substituent at the 2' position was the most effective inhibitor of Bla1 with Ki=0.057 microM. Inhibitors containing iron-chelating functional groups have previously been shown to work in combination with antibiotics to inhibit growth of antibiotic-resistant bacteria expressing beta-lactamase. The development of similar compounds, incorporating these types of substituents, may help overcome resistance to currently used antibiotics.
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Zanna
authors.initials: Z
authors.lastname: Beharry
authors.forename: Hansong
authors.initials: H
authors.lastname: Chen
authors.forename: Venkat R
authors.initials: VR
authors.lastname: Gadhachanda
authors.forename: John D
authors.initials: JD
authors.lastname: Buynak
authors.forename: Timothy
authors.initials: T
authors.lastname: Palzkill
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000201:enzymology*; D002614:Chelating Agents / Q000494:pharmacology; D019818:Clavulanic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007501:Iron / Q000737:chemistry / Q000493:pharmacokinetics; D007700:Kinetics; D008956:Models, Chemical; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010406:Penicillins / Q000494:pharmacology*; D013053:Spectrophotometry; D000078142:Tazobactam; D001618:beta-Lactamases / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D010406:Penicillins; D019818:Clavulanic Acid; D010397:Penicillanic Acid; D007501:Iron; D001618:beta-Lactamases; D000078142:Tazobactam