Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-beta-lactamase.
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.
Toney
J H
JH
Department of Biochemistry, Merck Research Laboratories, P. O. Box 2000, Rahway, NJ 07065-0900, USA. jeff_toney@merck.com
Fitzgerald
P M
PM
Grover-Sharma
N
N
Olson
S H
SH
May
W J
WJ
Sundelof
J G
JG
Vanderwall
D E
DE
Cleary
K A
KA
Grant
S K
SK
Wu
J K
JK
Kozarich
J W
JW
Pompliano
D L
DL
Hammond
G G
GG
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
D001713:Biphenyl Compounds; D015780:Carbapenems; D004791:Enzyme Inhibitors; C111888:L 159906; D013777:Tetrazoles; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases