Plant-derived antibiotic adjuvants against drug-resistant ESKAPE pathogens: a critical narrative review

Antimicrobial resistance in ESKAPE pathogens has intensified interest in antibiotic-adjuvant strategies that restore the activity of existing drugs rather than relying exclusively on de novo antibiotics. Plant-derived molecules are attractive in this context because chemically defined alkaloids, polyphenols, lignans, terpenoids, and related natural products can interfere with bacterial resistance systems, including multidrug efflux, outer-membrane integrity, lipid A modification, metallo-β-lactamase activity, biofilm formation, and quorum-regulated virulence. This critical narrative review evaluates plant-derived compounds as antibiotic adjuvants against drug-resistant ESKAPE pathogens, emphasizing the distinction between mechanistic plausibility and translational readiness. The literature base comprises in vitro susceptibility and synergy studies, time-kill experiments, biochemical and genetic mechanism studies, invertebrate infection models, and mammalian models. High-priority claims were cross-checked against the cited primary literature, and a targeted update through August 2026 was used to capture recent developments. The most persuasive preclinical examples are not uniformly distributed across phytochemical classes; rather, they cluster around specific resistance mechanisms and antibiotic-rescue problems. These include berberine-sulbactam combinations against multidrug-resistant Acinetobacter baumannii, mcr-1-directed or membrane-sensitizing adjuvants that restore polymyxins, NDM-1 inhibitors that protect carbapenems, and alkaloids that reverse tmexCD1-toprJ1-mediated tigecycline resistance. However, most evidence remains preclinical, and apparently strong in vitro synergy may depend on phytochemical concentrations that are difficult to achieve systemically. Future development therefore requires exposure-aware pharmacokinetics/pharmacodynamics (PK/PD) studies, rigorous toxicology, standardized compound characterization, resistance-evolution experiments, and infection models designed around clinically plausible dosing. Plant-derived compounds should currently be regarded primarily as a source of antibiotic-adjuvant scaffolds and mechanistic probes, with a smaller subset meriting structured translational development.