Gram-negative infections due to multi-drug resistant bacteria have been on the rise for some time and have the potential to lead to a public health crisis. Within the β-lactam class of antibiotics, resistance in Gram-negative organisms is primarily mediated by expression of β-lactamases. Particularly concerning is the emergence of metallo-β-lactamases (MBLs, e.g. New Delhi MBL, NDM-1), which have the power to inactivate all β-lactams aside from the monocyclic variant aztreonam. Unfortunately, aztreonam is unstable to many class A and C serine β-lactamases (SBLs), limiting its clinical use. One strategy to expand the utility of aztreonam is by co-administration with the serine β-lactamase inhibitor avibactam, currently under clinical investigation. We chose to address SBL stability directly through structural modification of the monobactam ring itself. Stability of analogs towards relevant β-lactamases was monitored by activity against an E. coli isogenic strain panel, each expressing a unique β-lactamase of the Ambler classes A, B, C and D. New monobactams demonstrated potent activity against a broad range of cephalosporin and carbapenem-resistant Enterobacteriaceae (CRE), with significantly improved stability against SBLs compared to aztreonam, while retaining stability towards MBLs. Most optimized analogs had limited activity against Gram-negative non-fermenters like Pseudomonas aeruginosa. Since induction of seizures through inhibition of the GABAA receptor is a class effect of β-lactam antibiotics, we monitored this in vitro using a GABAA yellow fluorescent protein-based assay and in vivo by intraventricular injection (IVC). The culmination of our efforts led to the identification of LYS228, a single agent monobactam with excellent activity against CRE and a low potential for CNS effects. Our data support the development of LYS228 for treatment of infections caused by CRE and extended spectrum β-lactamase (ESBL)-expressing Enterobacteriaceae. This agent is currently in phase I clinical trials.

Identification of LYS228: A Novel monobactam with activity against extended spectrum β-lactamase expressing and carbapenem-resistant enterobacteriaceae

254th National Meeting (2017)

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