Development\nof CGS-15943 Adjunctives for the Disruption\nof Plasmid Maintenance in Multidrug Resistant <i>E. coli</i>

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