In vitro activity of AVE1330A, an innovative broad-spectrum non-beta-lactam beta-lactamase inhibitor.
OBJECTIVE
Production of beta-lactamases is the main mechanism of beta-lactam resistance in Gram-negative bacteria. Despite the current use of clavulanic acid, sulbactam and tazobactam, the prevalence of class A and class C enzymes is increasing worldwide, demanding new beta-lactamase inhibitors. Here we report the antimicrobial properties of AVE1330A, a representative of a novel class of bridged bicyclico[3.2.1]diazabicyclo-octanones in combination with ceftazidime.


METHODS
IC(50) and kinetic parameters of the hydrolysis reaction were used to characterize beta-lactamase inhibition by AVE1330A. MICs for >600 strains were determined with the combination ceftazidime/AVE1330A at a fixed ratio of 4:1.


RESULTS
IC(50)s of AVE1330A for TEM-1 and P99 enzymes were 0.0023 mg/L (8 nM) and 0.023 mg/L (80 nM), compared with 0.027 mg/L (130 nM) and 205.1 mg/L (1 x 10(6) nM) of clavulanic acid and 0.013 mg/L (40 nM) and 1.6 mg/L (5000 nM) of tazobactam. A highly stable covalent complex led to a low turnover of AVE1330A. MICs of ceftazidime/AVE1330A for Enterobacteriaceae were at least eight-fold lower than those of ceftazidime alone. All of the Escherichia coli, Klebsiella pneumoniae, Citrobacter and Proteus mirabilis strains, including ceftazidime-resistant isolates, were inhibited at 4-8 mg/L. Only 2 mg/L were required to inhibit other Proteeae, Enterobacter, Salmonella and Serratia.


CONCLUSIONS
The combination of ceftazidime with AVE1330A exhibited broad-spectrum activity against Ambler class A- and class C-producing Enterobacteriaceae.
Bonnefoy
Alain
A
Aventis Pharma, Medicinal Chemistry, 102, Route de Noisy, 93235 Romainville Cedex, France. Alain.Bonnefoy@freesbee.fr
Dupuis-Hamelin
Claudine
C
Steier
Valérie
V
Delachaume
Carole
C
Seys
Catherine
C
Stachyra
Thérèse
T
Fairley
Monique
M
Guitton
Michèle
M
Lampilas
Maxime
M
D001381:Azepines / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D002442:Ceftazidime / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology; D019818:Clavulanic Acid / Q000494:pharmacology; D003640:Dealkylation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010406:Penicillins / Q000494:pharmacology; D010878:Piperacillin / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013463:Sulfuric Acid Esters / Q000494:pharmacology*; D000078142:Tazobactam; D001618:beta-Lactamases / Q000494:pharmacology*
C492231:AVE 1330A; D001381:Azepines; D002511:Cephalosporins; D004791:Enzyme Inhibitors; D010406:Penicillins; D013463:Sulfuric Acid Esters; D019818:Clavulanic Acid; D010397:Penicillanic Acid; D002442:Ceftazidime; D001618:beta-Lactamases; D000078142:Tazobactam; D010878:Piperacillin