Phytochemicals as Antibiotic Adjuvants: Mechanistic Insights into Synergistic Activity against Multidrug-Resistant Pathogens

Abstract

The global spread of multidrug-resistant bacterial pathogens has narrowed treatment options for common infections and threatens to reverse decades of progress in clinical medicine. Combination strategies that pair conventional antibiotics with non-antibiotic potentiators, commonly termed adjuvants, offer a pragmatic route to extend the useful life of existing drugs while new antimicrobial classes remain scarce. Plant-derived secondary metabolites, or phytochemicals, have attracted sustained attention as candidate adjuvants because many act through mechanisms distinct from, and complementary to, the primary targets of antibiotics. This review synthesises evidence on flavonoids, alkaloids, terpenoids and polyphenolic compounds that restore or enhance antibiotic activity against multidrug-resistant bacteria. The mechanistic basis of these interactions is examined across four broad categories: membrane and cell wall perturbation, efflux pump inhibition, enzymatic and gene-expression modulation, and quorum sensing or biofilm interference. Evidence from checkerboard and fractional inhibitory concentration index assays is critically appraised alongside emerging delivery strategies that address the poor aqueous solubility and limited bioavailability of many phytochemicals. Combinations involving methicillin-resistant Staphylococcus aureus, multidrug-resistant Pseudomonas aeruginosa and drug-resistant Mycobacterium tuberculosis are considered in depth, given their prominence on international priority pathogen lists. The review closes by identifying gaps in pharmacokinetic characterisation, standardisation of synergy testing, and clinical translation that must be addressed before phytochemical adjuvants can move from bench to bedside.