Synergistic Effects of Antibiotics and Plant-Derived Phytochemicals Against Antimicrobial-Resistant Microorganisms: Mechanisms, Recent Advances, and Future Perspectives

Abstract

AMR represents one of the greatest public health challenges worldwide. Its emergence also threatens the effectiveness of existing antibiotics and severely limits the ability to manage infectious diseases. Multidrug-resistant (MDR), extensively drugresistant (XDR), and pan-drug-resistant (PDR) pathogens are emerging at an unprecedented rate and call for urgent attention to the development of novel therapeutic strategies. An area of immense promise is the use of phytochemicals (plant-derived compounds) in combination with conventional antibiotics. Bioactive compounds, including flavonoids, alkaloids, phenolic acids, terpenoids, tannins, saponins, coumarins, and essential oils, possess broad-spectrum antimicrobial activity, which can work through multiple mechanisms such as disruption of bacterial membranes, inhibiting efflux pumps, interfering with quorum sensing and biofilm formation, attenuating virulence factors, and inhibiting resistance enzymes. In this review, we summarise the current evidence supporting the synergistic effects of antibiotic/phytochemical combinations against antimicrobial-resistant pathogens. Phytochemicals including curcumin, quercetin, epigallocatechin gallate, berberine, baicalein, thymol, carvacrol, eugenol, piperine, and allicin have been demonstrated to enhance the effective activity of beta-lactams, aminoglycosides, fluoroquinolones, tetracyclines, and glycopeptides against clinically relevant resistant pathogens. The antibiotic/phytochemical combinations reduce minimum inhibitory concentrations, increase antibiotic accumulation within cells, inhibit biofilm formation, and delay resistance development. While the preclinical data regarding these combinations is very promising; challenges remain due to limited clinical data regarding their standardisation, bioavailability, pharmacokinetics, herb-drug interaction, and potential side effects. Nanotechnology, artificial intelligence, omics, and precision medicine will continue to accelerate the development of safe and effective combinations of antibiotics and phytochemicals in the fight against AMR.