title: Targeting class A and C serine β-lactamases with a broad-spectrum boronic acid derivative.
abstract: Production of β-lactamases (BLs) is the most widespread resistance mechanism adopted by bacteria to fight β-lactam antibiotics. The substrate spectrum of BLs has become increasingly broad, posing a serious health problem. Thus, there is an urgent need for novel BL inhibitors. Boronic acid transition-state analogues are able to reverse the resistance conferred by class A and C BLs. We describe a boronic acid analogue possessing interesting and potent broad-spectrum activity vs class A and C serine-based BLs. Starting from benzo(b)thiophene-2-boronic acid (BZBTH2B), a nanomolar non-β-lactam inhibitor of AmpC that can potentiate the activity of a third-generation cephalosporin against AmpC-producing resistant bacteria, we designed a novel broad-spectrum nanomolar inhibitor of class A and C BLs. Structure-based drug design (SBDD), synthesis, enzymology data, and X-ray crystallography results are discussed. We clarified the inhibitor binding geometry responsible for broad-spectrum activity vs serine-active BLs using double mutant thermodynamic cycle studies.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco , 600 16th Street San Francisco, California 94143-2240, United States.
authors.forename: Donatella
authors.initials: D
authors.lastname: Tondi
authors.forename: Alberto
authors.initials: A
authors.lastname: Venturelli
authors.forename: Richard
authors.initials: R
authors.lastname: Bonnet
authors.forename: Cecilia
authors.initials: C
authors.lastname: Pozzi
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Costi
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D029968:Escherichia coli Proteins / Q000737:chemistry; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D012694:Serine / Q000378:metabolism*; D055672:Static Electricity; D013816:Thermodynamics; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D001897:Boronic Acids; D029968:Escherichia coli Proteins; D065093:beta-Lactamase Inhibitors; D012694:Serine; C412613:CTX-M-9 protein, E coli; C048795:AmpC beta-lactamases; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1