title: Structure of the extended-spectrum class C β-lactamase ADC-1 from Acinetobacter baumannii.
abstract: ADC-type class C β-lactamases comprise a large group of enzymes that are encoded by genes located on the chromosome of Acinetobacter baumannii, a causative agent of serious bacterial infections. Overexpression of these enzymes renders A. baumannii resistant to various β-lactam antibiotics and thus severely compromises the ability to treat infections caused by this deadly pathogen. Here, the high-resolution crystal structure of ADC-1, the first member of this clinically important family of antibiotic-resistant enzymes, is reported. Unlike the narrow-spectrum class C β-lactamases, ADC-1 is capable of producing resistance to the expanded-spectrum cephalosporins, rendering them inactive against A. baumannii. The extension of the substrate profile of the enzyme is likely to be the result of structural differences in the R2-loop, primarily the deletion of three residues and subsequent rearrangement of the A10a and A10b helices. These structural rearrangements result in the enlargement of the R2 pocket of ADC-1, allowing it to accommodate the bulky R2 substituents of the third-generation cephalosporins, thus enhancing the catalytic efficiency of the enzyme against these clinically important antibiotics.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Monolekha
authors.initials: M
authors.lastname: Bhattacharya
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Toth
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Nuno Tiago
authors.initials: NT
authors.lastname: Antunes
authors.affiliation: Stanford Synchrotron Radiation Lightsource, Stanford University, Menlo Park, California USA.
authors.forename: Clyde A
authors.initials: CA
authors.lastname: Smith
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Sergei B
authors.initials: SB
authors.lastname: Vakulenko
mesh_terms: D000151:Acinetobacter Infections / Q000201:enzymology / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D001051:Apoenzymes / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects; D002511:Cephalosporins / Q000494:pharmacology; D005810:Multigene Family; D013379:Substrate Specificity / Q000187:drug effects; D001618:beta-Lactamases / Q000737:chemistry* / Q000145:classification* / Q000235:genetics / Q000378:metabolism
chemical_list: D001051:Apoenzymes; D001426:Bacterial Proteins; D002511:Cephalosporins; C048795:AmpC beta-lactamases; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1
keywords: apoenzymes; class C β-lactamases