Development of CGS-15943 Adjunctives for the Disruption of Plasmid Maintenance in Multidrug Resistant E. coli.

Abstract

Carbapenemase producing Enterobacterales (CPEs) represent a group of multidrug resistant pathogens for which few, if any, therapeutics options remain available. CPEs generally harbor plasmids that encode resistance to last resort carbapenems and many other antibiotics. We previously performed a high throughput screen to identify compounds that can disrupt the maintenance and replication of resistance conferring plasmids through use of a synthetic screening plasmid introduced into Escherichia coli K-12 tolC cells. Despite being identified as a potent and selective antiplasmid agent through this screening effort, CGS-15943 was inactive in wild-type E. coli, suggesting that it is susceptible to TolC-mediated efflux. Herein, a series of analogues were developed to confirm the activity of the triazoloquinazoline chemotype and overcome efflux observed in wild-type E. coli K-12. Two analogues demonstrated superior antiplasmid activity to CGS-15943 in E. coli tolC mutants, while one compound displayed moderate activity in wild-type E. coli at low concentrations.