Introduction: The rapid spread of multidrug-resistant (MDR) bacteria poses a serious global health challenge, limiting the effectiveness of conventional antimicrobials. This review explores the potential of phytochemical synergy as an innovative therapeutic strategy to combat MDR infections through multi-targeted mechanisms. Methods: A comprehensive review of preclinical studies was conducted to evaluate the synergistic potential of phytochemical combinations, used either alone or alongside antibiotics, against MDR pathogens. Mechanistic insights, including biofilm disruption, efflux pump inhibition, and interference with microbial enzymes, were critically assessed. Results: Phytochemical combinations exhibited enhanced antimicrobial activity by targeting multiple resistance pathways. For example, 5′-methoxyhydnocarpin combined with berberine inhibited the Staphylococcus aureus NorA efflux pump, while doxycycline with baicalein disrupted biofilms and suppressed efflux in MDR Gram-negative bacteria. Flavonoids, such as quercetin and kaempferol, impaired microbial enzyme function and membrane integrity. Plant extracts from Cinchona officinalis and Lippia multiflora showed synergistic effects with antibiotics against resistant strains, including Pseudomonas aeruginosa Discussion: Phytochemical synergy offers a sustainable, multi-targeted approach to enhance antimicrobial efficacy, delay resistance development, and minimize toxicity. However, clinical translation remains challenging due to variability in phytochemical content, lack of standardization, limited pharmacokinetic and toxicological data, and scarcity of clinical trials. Conclusion: Phytochemical combinations represent a promising strategy against MDR pathogens. This review underscores the need for future research to prioritize standardization, pharmacokinetic profiling, clinical validation, and integration of omics technologies, AI-driven modeling, and nanoformulations to optimize the therapeutic potential of phytochemical combinations.
Ahmad et al. (Wed,) studied this question.