ceftazidime and Seizures

Metallo-β-lactamases (MBLs), such as New Delhi metallo-β-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative bacteria to all classes of β-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobactam drugs like aztreonam have limited clinical utility against MBL-expressing strains because they are impacted by serine β-lactamases (SBLs), which are often co-expressed in clinical isolates. Here, we optimized novel monobactams for stability against SBLs, which led to the identification of LYS228 (compound 31). LYS228 is potent in the presence of all classes of β-lactamases and shows potent activity against carbapenem-resistant isolates of Enterobacteriaceae (CRE).

Topics: Animals; Anti-Bacterial Agents; Aztreonam; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; CHO Cells; Cricetulus; Drug Stability; Escherichia coli; Female; Humans; Meropenem; Mice; Microbial Sensitivity Tests; Molecular Structure; Monobactams; Pseudomonas aeruginosa; Receptors, GABA-A; Seizures; Structure-Activity Relationship; Thienamycins

We describe herein the synthesis and biological evaluation of a series of novel cephalosporins with potent activity against Pseudomonas aeruginosa. Introduction of various amino groups to the 4-position of a 3-amino-2-methylpyrazole cephalosporin 3-side chain resulted in enhanced MIC values against multiple Pseudomonas aeruginosa strains and ultimately led to the discovery of FR264205 (15) with excellent anti-bacterial activity and weak convulsion effect by direct intracerebroventricular injection assay.

Topics: Animals; Anti-Bacterial Agents; Ceftazidime; Cephalosporins; Drug Design; Drug Evaluation, Preclinical; Mice; Pseudomonas aeruginosa; Seizures; Structure-Activity Relationship