In vitro activity of AVE1330A, an innovative broad-spectrum non-beta-lactam beta-lactamase inhibitor.

OBJECTIVES: 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. MATERIALS AND 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. CONCLUSION: The combination of ceftazidime with AVE1330A exhibited broad-spectrum activity against Ambler class A- and class C-producing Enterobacteriaceae.

Design and synthesis of bridged gamma-lactams as analogues of beta-lactam antibiotics.

Anti-Bredt bridged bicyclo[3.2.1] gamma-lactams were designed as inhibitors of penicillin binding proteins (PBPs). The compounds were prepared by a carbenoid insertion into a lactam N-H bond. Their weak antibacterial activity could either be explained by a poor chemical stability or by unfavorable steric interactions of the methylene bridge of the gamma-lactam with the targeted enzymes.

Synthesis of 9-oxime-11,12-carbamate ketolides through a novel N-deamination reaction of 11,12-hydrazonocarbamate ketolide.

A series of 9-oxime-11,12-carbamate ketolides was synthesized for the first time through a key 11,12-hydrazonocarbamate intermediate that was first oximated and further deaminated to give the corresponding carbamate. The N-N bond cleavage was achieved through an original new reaction using glycoaldehyde dimer as deaminating reagent. The new compounds synthesized were shown to display improved antibacterial activities against Streptococcus pneumoniae and S. pyogenes resistant to erythromycin.

Coniosetin, a novel tetramic acid antibiotic from Coniochaeta ellipsoidea DSM 13856.

The coprophilic ascomycete Coniochaeta ellipsoidea DSM 13856 forms the new antibiotic coniosetin (1) in surface cultures grown on a medium containing malt extract and oatmeal. The structure of the compound C25H35NO4, MW 413, was determined by 2D-NMR and mass spectrometric studies. Coniosetin belongs to the class of tetramic acids; it consists of a substituted aliphatic bicyclic ring system linked to a tetramic acid subunit through a carbonyl center. The absolute configuration was determined by measuring its circular dichroism spectrum and comparing the data with those of equisetin. Coniosetin has a pronounced antibacterial and antifungal action, inhibiting even multi drug-resistant strains of Staphylococcus aureus at a concentration of 0.3 microg/ml, though it is inactive against Gram-negative bacteria.