carumonam 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

The behavioural and electrocortical effects of two monobactam derivatives were studied after intraperitoneal (ip) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures, and in C57 and Swiss mice, two strains not prone to seizure. DBA/2 mice were more susceptible than Swiss and C57 mice to seizures induced by aztreonam or carumonam. No significant differences were observed between seizures elicited by aztreonam and carumonam in animals (DBA/2 only) administered intracerebroventricularly or ip. Although the main mechanism for seizure-like activity of monobactams cannot be easily determined, we believe that several mechanisms may be involved. An increased excitation of the central nervous system (CNS) by inhibition of GABA binding to receptors and a slow clearance of aztreonam and carumonam from the CNS may be postulated.

Topics: Acoustic Stimulation; Animals; Aztreonam; Cerebral Cortex; Convulsants; Electroencephalography; Injections, Intraventricular; Mice; Mice, Inbred DBA; Mice, Inbred Strains; Monobactams; Seizures