title: Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-beta-lactamase.
abstract: BACKGROUND
  High level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems.
  
  
  RESULTS
  Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts directly with one of the two zinc atoms in the active site, replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro correlates well with antibiotic sensitization of resistant B. fragilis.
  
  
  CONCLUSIONS
  BPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin.
authors.affiliation: Department of Biochemistry, Merck Research Laboratories, P. O. Box 2000, Rahway, NJ 07065-0900, USA. jeff_toney@merck.com
authors.forename: J H
authors.initials: JH
authors.lastname: Toney
authors.forename: P M
authors.initials: PM
authors.lastname: Fitzgerald
authors.forename: N
authors.initials: N
authors.lastname: Grover-Sharma
authors.forename: S H
authors.initials: SH
authors.lastname: Olson
authors.forename: W J
authors.initials: WJ
authors.lastname: May
authors.forename: J G
authors.initials: JG
authors.lastname: Sundelof
authors.forename: D E
authors.initials: DE
authors.lastname: Vanderwall
authors.forename: K A
authors.initials: KA
authors.lastname: Cleary
authors.forename: S K
authors.initials: SK
authors.lastname: Grant
authors.forename: J K
authors.initials: JK
authors.lastname: Wu
authors.forename: J W
authors.initials: JW
authors.lastname: Kozarich
authors.forename: D L
authors.initials: DL
authors.lastname: Pompliano
authors.forename: G G
authors.initials: GG
authors.lastname: Hammond
mesh_terms: D001441:Bacteroides fragilis / Q000187:drug effects* / Q000201:enzymology; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D015780:Carbapenems / Q000378:metabolism* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology*; D018440:beta-Lactam Resistance; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D015780:Carbapenems; D004791:Enzyme Inhibitors; C111888:L 159906; D013777:Tetrazoles; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases