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In the current study, the combination of amikacin and nitrofurantoin is found to synergistically eradicate Gram\u2010negative uropathogens in vitro and in vivo. The mechanistic analysis demonstrates that the amikacin, as an aminoglycoside, induced bacterial envelope stress by introducing mistranslated proteins, thereby constitutively activating the <jats:italic>cpxA<\/jats:italic>\/<jats:italic>R<\/jats:italic> two\u2010component system (Cpx signaling). The activation of Cpx signaling stimulates the expression of bacterial major nitroreductases (<jats:italic>nfsA<\/jats:italic>\/<jats:italic>nfsB<\/jats:italic>) through <jats:italic>soxS<\/jats:italic>\/<jats:italic>marA<\/jats:italic> regulons. As a result, the <jats:italic>CpxA\/R<\/jats:italic>\u2010dependent nitroreductases overexpression generates considerable quantity of lethal reactive intermediates via nitroreduction and promotes the prodrug activation of nitrofurantoin. As such, these actions together disrupt the bacterial cellular redox balance with excessively\u2010produced reactive oxygen species (ROS) as \u201cDomino effect\u201d, accelerating the clearance of uropathogens. Although aminoglycosides are used as proof\u2010of\u2010principle to elucidate the mechanism, the synergy between nitrofurantoin is generally applicable to other Cpx stimuli. 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