Berberine as a therapeutic alkaloid against ESKAPE and multiple drug-resistant bacteria: a comprehensive review

The rise of multidrug-resistant (MDR) bacteria, especially the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), is one of the most significant issues in modern medicine. Berberine, a quaternary ammonium isoquinoline alkaloid derived from a number of plant species, has been shown to be an effective therapeutic agent against resistant pathogens. This review provides a detailed overview of the chemical structure, pharmacology, and mechanism of action for berberine against ESKAPE and other MDR bacteria. The literature suggests that berberine displays antimicrobial activity through several mechanisms, including damaging the membrane, inhibiting DNA gyrase, inhibiting protein synthesis, and inhibiting efflux pumps. Berberine shows considerable synergy when combined with standard antibiotics, which could reverse antibiotic resistance. Notably, berberine demonstrates synergistic effects with β-lactam antibiotics, reducing fractional inhibitory concentration (FIC) indices to 0.25-0.5, thereby enhancing antibacterial efficacy against multidrug-resistant strains. Although berberine exhibits remarkable in vitro antimicrobial activity, its very poor systemic bioavailability (< 1%) results in a more than 1000-fold PK-PD gap between achievable plasma levels and effective MIC values. The clinical and preclinical studies show a good safety profile for use with minimal toxicity at therapeutic concentrations. Therefore, the current clinical use of berberine is limited to adjuvant, topical, or gastrointestinal applications rather than systemic monotherapy. The routes of delivery, pharmacokinetic characteristics, and standardization of treatment remain obstacles for wider application. This review collates the current evidence that supports berberine as an alternative or adjunct therapy to combat the worldwide issue of antibiotic resistance and also indicates areas where further research is required to bring therapies to the clinical level.