Natural Product-Based Strategies for Combating Antimicrobial Resistance in ESKAPE Pathogens

The increase of antimicrobial resistance (AMR), particularly among the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. poses a critical global threat to public health by severely limiting effective therapeutic options. These pathogens employ diverse and efficient survival strategies, including drug-degrading enzymes, target modification, porin loss, efflux pump overexpression, and biofilm formation, leading to multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan-resistant clinical phenotypes. As conventional antibiotic discovery slows and treatment failures rise, natural products have re-emerged as a promising source of chemically diverse leads with antibacterial activity. Plants and microbes biosynthesize structurally diverse secondary metabolites such as polyketides, alkaloids, flavonoids, phenolics, terpenoids, and saponins, many of which exhibit broad-spectrum antibacterial activity and synergize with existing antibiotics while exerting reduced selective pressure for resistance. Several compounds demonstrated potent antibacterial activity with MIC values ranging from 0.1 to 32 µg/mL, highlighting their therapeutic potential. This review provides a comprehensive analysis of natural product-based strategies against ESKAPE pathogens, highlighting their mechanisms of action: membrane disruption, inhibition of efflux pumps, interference with DNA/protein synthesis, suppression of quorum sensing, and inhibition of biofilm formation. Special emphasis is placed on alkaloids, flavonoids, and terpenoids whose antibacterial potential is closely linked to defined structure-activity relationships (SAR). Alkaloids such as berberine, sanguinarine, and conessine show potent activity by targeting cell wall integrity, FtsZ-mediated division, and efflux systems, while specific flavonoid subclasses exhibited enhanced antibacterial potency through key structural features such as 5,7-dihydroxylation, prenylation, and optimized B-ring substitutions. Numerous natural products discussed demonstrate clinically relevant activity against MDR S. aureus, carbapenem-resistant K. pneumoniae, A. baumannii, and P. aeruginosa, supporting their potential as lead compounds or adjuvant agents.