title: Class D β-lactamases do exist in Gram-positive bacteria.
abstract: Production of β-lactamases of one of four molecular classes (A, B, C and D) is the major mechanism of bacterial resistance to β-lactams, the largest class of antibiotics, which have saved countless lives since their inception 70 years ago. Although several hundred efficient class D enzymes have been identified in Gram-negative pathogens over the last four decades, none have been reported in Gram-positive bacteria. Here we demonstrate that efficient class D β-lactamases capable of hydrolyzing a wide array of β-lactam substrates are widely disseminated in various species of environmental Gram-positive organisms. Class D enzymes of Gram-positive bacteria have a distinct structural architecture and employ a unique substrate-binding mode that is quite different from that of all currently known class A, C and D β-lactamases. These enzymes thus constitute a previously unknown reservoir of novel antibiotic-resistance enzymes.
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: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Nichole K
authors.initials: NK
authors.lastname: Stewart
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Hilary
authors.initials: H
authors.lastname: Frase
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: 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: D000595:Amino Acid Sequence; D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D001406:Bacillaceae / Q000201:enzymology / Q000235:genetics; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D006094:Gram-Positive Bacteria / Q000201:enzymology* / Q000235:genetics; D006868:Hydrolysis; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D001618:beta-Lactamases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D047090:beta-Lactams / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D047090:beta-Lactams; D001120:Arginine; D001618:beta-Lactamases