Plant-Derived Compounds as Antibiotic Adjuvants Against Drug-Resistant ESKAPE Pathogens: Mechanisms of Action, Synergistic Strategies, and Translational Challenges

Background/Objectives: Antimicrobial resistance among ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens has become a major global health threat, significantly reducing the effectiveness of conventional antibiotics. Plant-derived compounds have emerged as promising antibiotic adjuvants capable of restoring antibiotic activity through multiple resistance-modulating mechanisms. This review aims to critically evaluate the current evidence regarding phytochemicals that enhance antibiotic efficacy against drug-resistant ESKAPE pathogens. Methods: Relevant studies investigating plant-derived compounds with antibiotic adjuvant activity against ESKAPE pathogens were identified and critically analyzed. Particular attention was given to mechanisms of action, synergistic interactions with conventional antibiotics, structure–activity relationships, and translational evidence from in vivo studies. Results: Numerous phytochemicals have demonstrated the ability to potentiate antibiotic activity through efflux pump inhibition, biofilm disruption, membrane permeabilization, and quorum sensing interference. For instance, the flavonoid quercetin inhibits the NorA efflux pump in Staphylococcus aureus, restoring ciprofloxacin susceptibility, while the sulfur-containing compound ajoene from garlic disrupts quorum sensing in Pseudomonas aeruginosa, sensitizing biofilms to tobramycin. Although several compounds exhibit promising synergistic effects in vitro, significant barriers remain regarding bioavailability, standardization, pharmacokinetics, and clinical translation. Conclusions: Plant-derived antibiotic adjuvants represent a promising strategy to combat multidrug-resistant ESKAPE pathogens. However, greater emphasis on translational research, standardized methodologies, and clinically relevant experimental models is required to facilitate their development toward therapeutic applications.