New Multitarget Inhibitor Potentiates Antimicrobial Activity of Aztreonam against Metallo-β-lactamase-Producing <i>Pseudomonas aeruginosa</i> Including IMP-Types

Combination of aztreonam (ATM) and avibactam (AVI) was proven to be synergistic against metallo-β-lactamase (MBL)-producing <i>Enterobacteriaceae</i>. However, in the case of <i>Pseudomonas aeruginosa</i> (PA), ATM-potentiation by AVI can hardly be achieved because PA has complex resistance mechanisms. In this study, we identified 3,7-bis-<i>O</i>-substituted difluoroquercetin derivatives <b>9</b> and <b>12</b> as new ATM-potentiating agents against the MBL-producing PAs through the simultaneous inhibition of NDM-1, OXA-10, and efflux pumps. Even though the inhibitory activity of <b>9</b> and <b>12</b> against the ATM-hydrolyzing β-lactamases (NDM-1 and OXA-10) as well as the efflux pumps is moderate, the simultaneous inhibition of multiple resistance mechanisms seems to result in remarkable potentiation of ATM against this formidable pathogen. Particularly, the IMP-producing CRPAs resistant to the most promising MBL-inhibitors were sensitized to ATM upon combination with compounds <b>9</b> and <b>12</b>. Compound <b>9</b> demonstrated potent <i>in vivo</i> rescue of ATM activity in a murine thigh infection model.