Plant-Derived Multi-Target Inhibitors as Novel Drug Target Strategies Against Drug-Resistant TB and Bacterial Pathogens

The rapid emergence of drug-resistant Mycobacterium tuberculosis and other bacterial pathogens has significantly reduced the effectiveness of conventional antimicrobial therapies. Single-target antibiotics are particularly vulnerable to resistance due to mutations, efflux mechanisms, and metabolic adaptation. This review highlights plant-derived secondary metabolites as promising multitarget antimicrobial agents that simultaneously disrupt key bacterial processes, including DNA replication, cell wall biosynthesis, energy metabolism, and virulence regulation. Evidence from experimental and computational studies demonstrates that major phytochemical classes, alkaloids, flavonoids, terpenoids, and phenolics, exhibit multitarget activity by inhibiting DNA gyrase, suppressing efflux pumps, disrupting membrane integrity, and inducing redox imbalance. Notably, compounds such as berberine, quercetin, curcumin, and thymol have been shown to enhance intracellular drug accumulation, inhibit biofilm formation, and restore antibiotic sensitivity in drug-resistant strains. Computational approaches, including molecular docking, molecular dynamics simulations, network pharmacology, and the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling, further support these findings by revealing strong binding affinities, stable ligand–target interactions, and favorable pharmacokinetic properties of selected phytochemicals against critical M. tuberculosis targets such as Enoyl-ACP reductase (InhA) and Decaprenylphosphoryl-β-D-ribose 2′-epimerase 1 (DprE1). Thus, these findings demonstrate that plant-derived multitarget inhibitors not only interfere with multiple essential and adaptive bacterial pathways but also reduce the likelihood of resistance development. This positions them as promising candidates for next-generation anti-infective therapies and adjuncts to existing treatment regimens.