Herbal extracts as antibiotic adjuvants against ESKAPE pathogens: mechanisms and therapeutic potential

• Herbal extracts act as antibiotic adjuvants against ESKAPE pathogens • Synergistic herbal-antibiotic effects arise from multi-target mechanisms • AI accelerates the effective discovery of antibiotic adjuvants from herbal sources • Standardized process and elucidated mechanisms drive herbal clinical translation The escalating crisis of antimicrobial resistance, particularly driven by ESKAPE pathogens, poses a serious threat to global public health. With the stagnant pipeline of novel antibiotic discovery, repurposing herbal extracts as antibiotic adjuvants to revive existing therapies is a promising strategy. This review systematically elaborates the multi-faceted mechanisms by which herbal extracts and their bioactive constituents counteract multi-drug resistance in ESKAPE pathogens. These mechanisms include the inhibition of antibiotic-degrading enzymes, alteration of bacterial membrane permeability to facilitate antibiotic uptake, blockade of major efflux pumps that expel multiple drug classes, and counteraction of antibiotic target modification. Furthermore, the roles of phytochemicals in inhibiting and dispersing biofilms, attenuating virulence factors, disrupting quorum sensing, and promoting reactive oxygen species accumulation are discussed. Despite the potent synergistic potential demonstrated by various lead compounds (such as andrographolide, quercetin, berberine, thymol, curcumin, eugenol, and oleanolic acid) in preclinical models, their progression through the translational pipeline is frequently hindered by inconsistent manufacturing standards and the inherent complexity of elucidating their polypharmacological mechanisms. Advancing the clinical utility of these herbal adjuvants necessitates a multidimensional approach, including artificial intelligence-driven screening, in-depth mechanistic studies of multi-component synergy, and comprehensive clinical assessments. Accordingly, this review aimed to establish a rigorous foundation for designing next-generation anti-infective therapies based on herb–antibiotic synergy.