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Titolo:
ANTIBIOTIC SENSITIZATION USING BIPHENYL TETRAZOLES AS POTENT INHIBITORS OF BACTEROIDES-FRAGILIS METALLO-BETA-LACTAMASE
Autore:
TONEY JH; FITZGERALD PMD; GROVERSHARMA N; OLSON SH; MAY WJ; SUNDELOF JG; VANDERWALL DE; CLEARY KA; GRANT SK; WU JK; KOZARICH JW; POMPLIANO DL; HAMMOND GG;
Indirizzi:
MERCK RES LABS,DEPT BIOCHEM,POB 2000 RAHWAY NJ 07065 MERCK RES LABS,DEPT BASIC CHEM RAHWAY NJ 07065
Titolo Testata:
Chemistry & biology
fascicolo: 4, volume: 5, anno: 1998,
pagine: 185 - 196
SICI:
1074-5521(1998)5:4<185:ASUBTA>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
IMIPENEM-CILASTATIN; PHARMACOKINETIC PROPERTIES; ANTIBACTERIAL ACTIVITY; THERAPEUTIC EFFICACY; RECEPTOR ANTAGONISTS; RENAL DIPEPTIDASE; AUTOMATED DOCKING; RESISTANCE; THIENAMYCIN;
Keywords:
ANTIBIOTIC RESISTANCE; BIPHENYL TETRAZOLES; CRYSTAL STRUCTURE; ENZYME INHIBITORS; METALLO-BETA-LACTAMASE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
42
Recensione:
Indirizzi per estratti:
Citazione:
J.H. Toney et al., "ANTIBIOTIC SENSITIZATION USING BIPHENYL TETRAZOLES AS POTENT INHIBITORS OF BACTEROIDES-FRAGILIS METALLO-BETA-LACTAMASE", Chemistry & biology, 5(4), 1998, pp. 185-196

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) area 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 09/04/20 alle ore 19:51:02