Preserving beta-lactam utility vs pathogens producing any class of beta-lactamase

DESCRIPTION provided by applicant Multi drug resistance in Enterobacteriaceae is regarded as a healthcare crisis This crisis has been further amplified by the recent emergence of the NDM andquot super bug geneandquot 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 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 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 and VNRX 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 andquot Finalistsandquot and drive this compound through IND enabling studies to an Investigational New Drug filing PUBLIC HEALTH RELEVANCE The NDM andquot Super bug geneandquot 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 but they are degraded by other lactamases invariably co expressed with NDM Our combination product consisting of a novel broad spectrum serine lactamase inhibitor with Aztreonam will directly address this growing medical crisis