Multi-drug resistance in Enterobacteriaceae is regarded as a healthcare crisis. This crisis has been further amplified by the recent emergence of the NDM-1 "super-bug gene", a zinc-based metallo-?-lactamase (Amber Class B), in Enterobacteriaceae. Members of this family of resistance enzymes are found on promiscuous plasmids with other MDR resistance mechanisms, and are rapidly spreading throughout Enterobacteriaceae. NDM-1 hydrolyzes all subclasses of ?-lactams (penicillins, cephalosporins and carbapenems) with the exception of monobactams (e.g., Aztreonam). However, Aztreonam remains susceptible to the majority of serine-based ?-lactamases that are invariably found co-expressed with NDM-1. The combination of a new generation, broad-spectrum serine ?-lactamase inhibitor with Aztreonam would provide physicians with a new weapon to address this growing crisis. In the Phase I work, we identified two potential pre-development candidates (VNRX-5109 and VNRX- 5119) exceeding established success criteria. These compounds demonstrate potent and selective inhibitory activity against key serine-?-lactamases such as Ambler Class A extended-spectrum ?-lactamases (ESBLs, e.g., SHV, CTXM, TEM), Class A carbapenemases (KPC-type), Class C cephalosporinases (e.g., AmpC, CMY, FOX) and Class D oxacillinases and potent rescue of Aztreonam activity in recent and representative clinical isolates of Enterobacteriaceae expressing mixed serine and metallo-?-lactamases. Moreover, the compounds rescue Aztreonam efficacy in vivo a murine septicemia model utilizing mixed serine- and metallo- ?-lactamase-expressing strains of Enterobacteriaceae. Preliminary pharmacokinetic assessments in mice suggest that the compounds will be compatible with t.i.d. dosing with Aztreonam. We are now positioned to advance one of these potential pre-development candidates through preclinical development. The Phase II application endeavors to select a pre-development candidate from these two "Finalists" and drive this compound through IND-enabling studies to an Investigational New Drug filing.
The NDM-1 Super-bug gene is spreading throughout Enterobacteriaceae and poses a serious threat to ?- lactam efficacy in both the hospital and community settings. The monobactams are not susceptible to hydrolysis by NDM-1, but they are degraded by other ?-lactamases invariably co-expressed with NDM-1. Our combination product consisting of a novel, broad-spectrum serine-?-lactamase inhibitor with Aztreonam will directly address this growing medical crisis.