Recent investigations have revealed that a combination of aztreonam (ATM), a monobactam antibiotic, with a β-lactamase inhibitor (ceftazidime/avibactam, CAZ/AVI) can be used for the treatment of infections caused by carbapenemases-resistant E. coli. However, due to the complex resistance mechanism, the metallo-carbapenemase-producing Pseudomonas aeruginosa are not susceptible to ATM/CAZ/AVI combinations to leave polymyxin as the only treatment option. In this context, it is urgently required to discover novel combination antibiotic therapy against the formidable foe, and there have been numerous efforts to discover novel inhibitors against the efflux pumps and carbapenemases, the key players in carbapenemases resistance in Gram negative bacteria. In this study, we discovered that a new class of compounds with a modified quercetin scaffold serve as hereto unknown dual inhibitors of the efflux pumps and carbapenemases. Worth to note is that they have broad-spectrum inhibitory activity against various carbapenemases including the hard-to-inhibit metallo-carbapenemases. In addition, the dual inhibitor significantly enhanced the antimicrobial activity of ATM against the metallo-carbapenemase-producing P. aeruginosa and, upon combination with the dual inhibitor, the MIC of ATM decreased below its clinical breakpoint (1 mg/L).