Natural-Product-Derived Antimicrobial Adjuvants to Reverse Plasmid-Mediated Bacterial Resistance

The clinical efficacy of β-lactams, polymyxins, and tetracyclines is especially increasingly compromised by plasmid-mediated resistance mechanisms. These include but are not limited to expression of β-lactamases (BLs), MCRs (encoded by the <i>mcrs</i> colistin resistance gene), and TetX (encoded by the <i>tet</i>(X3)/<i>tet</i>(X4) tetracycline resistance gene), which have constituted a significant menace to public health and food safety, triggering urgent concern worldwide. Combating this crisis requires innovative approaches, among which the development of antimicrobial adjuvants that synergize with existing antibiotics holds particular promise for reclaiming lost therapeutic efficacy. This review systematically summarizes the plasmid-mediated resistance mechanisms that inactivate β-lactams, polymyxins, and tetracyclines. Furthermore, we provide a detailed overview of all identified natural product chemotypes capable of inhibiting SBLs, MBLs, MCRs, and Tet(X3)/Tet(X4) enzymes or functioning as antimicrobial adjuvants along with their mechanisms of action. These findings establish fundamental principles to guide the development of broad-spectrum antimicrobial adjuvants aimed at counteracting plasmid-mediated bacterial resistance.