ANTIBIOTIC SENSITIZATION USING BIPHENYL TETRAZOLES AS POTENT INHIBITORS OF BACTEROIDES-FRAGILIS METALLO-BETA-LACTAMASE

Background: High level resistance to carbapenem antibiotics in gram ne gative bacteria such as Bacteroides fragilis is caused, in part, by ex pression 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 antibacte rial activity of carbapenems. Results: Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-la ctamase identified through screening and predicted using molecular mod eling of the enzyme structure. The X-ray crystal structure of the enzy me bound to the BPT L-159,061 shows that the tetrazole moiety of the i nhibitor interacts directly with one of the two zinc atoms in the acti ve site, replacing a metal-bound water molecule. Inhibition of metallo -beta-lactamase by BPTs in vitro correlates well with antibiotic sensi tization of resistant B. fragilis. Conclusions: BPT inhibitors can sen sitize a resistant B. fragilis clinical isolate expressing metallo-bet a-lactamase to the antibiotics imipenem or penicillin G but not to rif ampicin.