Novel Metallo-beta-lactamase Inhibitors

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DESCRIPTION (provided by applicant): ¿-lactam resistance conferred by zinc-based metallo-¿-lactamases (Amber Class B) is an emerging global health problem1-3. Members of this family of enzymes such as NDM-1 are found on mobile genetic elements which are rapidly spreading in Enterobacteriaceae and threaten to erode the future utility of the ¿- lactam antibiotics (i.e. penicillins, cephalosporins, carbapenems) both in hospital and community settings1,5,6. The concern now is that, in the absence of clinically available MBL inhibitors, MBLs could become the dominant carbapenemases in clinical settings. As there are currently no MBL inhibitors in pharmaceutical development, there is an urgent need for new initiatives to address this growing issue and protect the lifespan of all ¿-lactams. This Phase I SBIR Application focuses on the advancement of a novel first-in-class chemical series of potent metallo-¿-lactamase inhibitors (MBLIs). We have generated cell active highly soluble advanced lead compounds with i) the highest reported affinity for VIM-2 (Ki of 0.002 ¿M) and NDM-1 (estimated Ki of 0.05- 0.08 ¿M), ii) greater than 5,000-fold selectivity versus mammalian metalloenzymes, iii) the ability to improve imipenem activity by up to 128-fold in E. coli, iv) significant imipenem rescue activity in a collection of NDM-1 and VIM-expressing clinical isolates of Enterobacteriaceae and Pseudomonas spp., and v) no cytotoxicity against mammalian cell lines. This is the first report of an inhibitor series capable of protecting a carbapenem in NDM-1 expressing bacteria. The goal of this SBIR application is to progress current Advanced Lead Metallo-¿-Lactamase inhibitors to Preclinical Candidate "Finalists" possessing potent inhibitory activity towards key MBLs including NDM-1 and VIM enzymes to help protect carbapenem efficacy in Enterobacteriaceae and Pseudomonas spp. During the 2-year timeframe of the Application, we intend to advance the chemical optimization of this series by increasing potency to NDM-1 and VIM-variants, assess MBL spectrum across other subclass B1 MBLs, maintain selectivity versus mammalian metalloenzymes, increase imipenem rescue capacity in MBL expressing clinical isolates and obtain proof of in vivo efficacy of a finalist compound in a murine septicemia model of infection. Success will trigger the submission of a phase II proposal containing late stage Lead optimization activities directed at selecting and advancing a Preclinical Candidate to IND submission.