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The tripartite efflux pump AcrAB-NodT confers adaptive MDR in the polarized \u03b1-proteobacterium <jats:italic>Caulobacter crescentus<\/jats:italic> via transcriptional induction by first-generation quinolone antibiotics. We discovered that overexpression of AcrAB-NodT by mutation or exogenous inducers confers resistance to cephalosporin and penicillin (\u03b2-lactam) antibiotics. Combining 2-step mutagenesis-sequencing (Mut-Seq) and cephalosporin-resistant point mutants, we dissected how TipR uses a common operator of the divergent <jats:italic>tipR<\/jats:italic> and <jats:italic>acrAB-nodT<\/jats:italic> promoter for adaptive and\/or potentiated AcrAB-NodT-directed efflux. Chemical screening identified diverse compounds that interfere with DNA binding by TipR or induce its dependent proteolytic turnover. 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