Plant-Derived Compounds as Antibiotic Adjuvants Against Drug-Resistant ESKAPE Pathogens: Mechanisms of Action, Synergistic Strategies, and Translational Challenges

PLANT-DERIVED THERAPEUTICS AS A NOVEL STRATEGY TO COMBAT ANTIMICROBIAL RESISTANCE: CURRENT ADVANCES AND FUTURE PERSPECTIVE

Antimicrobial resistance (AMR) has emerged as one of the most critical global public health challenges of the 21st century, significantly compromising the effectiveness of conventional antibiotics and increasing morbidity, mortality, and healthcare costs worldwide. In this context, plant-derived therapeutics have gained considerable scientific attention owing to their diverse bioactive phytoconstituents and broad-spectrum antimicrobial potential. Medicinal plants contain a wide range of secondary metabolites, including alkaloids, flavonoids, terpenoids, phenolic compounds, tannins, saponins, and essential oils, which exhibit antimicrobial activity through multiple mechanisms, such as disruption of microbial cell membranes, inhibition of biofilm formation, suppression of quorum sensing, modulation of efflux pumps, and interference with nucleic acid and protein synthesis. Additionally, synergistic combinations of phytochemicals with conventional antibiotics have demonstrated promising potential for enhancing antibiotic activity and overcoming specific resistance mechanisms. This review comprehensively discusses recent advances in plant-derived antimicrobial agents, their mechanisms of action, activity against MDR pathogens, antibiotic-adjuvant potential, and emerging technological approaches for improving their therapeutic efficacy. Overall, plant-derived therapeutics represent a promising and sustainable avenue for the discovery and development of complementary antimicrobial strategies to address the growing global burden of AMR.

Natural Compounds of Plant Origin–Promising Agents in the Fight Against Antibiotic Resistance

MicroRNAs as novel therapeutics against multidrug-resistant ESKAPE pathogens: mechanisms, challenges, and future directions.

BACKGROUND Multidrug-resistant (MDR) ESKAPE pathogens, including Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P. aeruginosa, and Enterobacter spp., pose a critical global health threat. OBJECTIVE This narrative review evaluates microRNAs (miRNAs) as novel antibacterial agents against MDR ESKAPE, focusing on their mechanisms of action, preclinical efficacy, delivery innovations, and translational barriers. METHODS PubMed and Google Scholar were searched using terms related to miRNA biology, antibacterial activity, ESKAPE pathogens, and delivery platforms RESULTS: miRNAs exert antibacterial effects through three mechanisms: innate and adaptive immune modulation, regulation of host antibacterial pathways (including antimicrobial peptide production), and direct cross-kingdom bacterial mRNA silencing with biofilm disruption. Preclinical evidence highlights key candidates: let-7b-5p achieved a 90% reduction in P. aeruginosa biofilm and restored aztreonam sensitivity, and miR-101-3p, delivered via DNA tetrahedron nanostructures, suppressed polymicrobial biofilms in cystic fibrosis (CF) models. The Rocket-miR platform identified miRNA candidates across all ESKAPE organisms, including miR-877-5p and miR-3127-5p, which target carbapenem-resistant K. pneumoniae and vancomycin-resistant E. faecium. The core translational challenges include miRNA instability, limited cellular uptake, off-target effects, and undefined regulatory pathways. Nanocarrier-based delivery, exosomal platforms, and machine learning-assisted target prediction offer promising solutions to these challenges. CONCLUSION Current preclinical evidence suggests that miRNAs hold promise as early-stage candidate antibacterial agents through immunomodulation, host pathway regulation, and direct bacterial gene silencing with biofilm disruption. However, no miRNA-based antibacterial therapy has entered clinical evaluation, and substantial translational barriers, including delivery challenges, off-target effects, and undefined regulatory pathways, must be addressed before clinical application can be considered.

Exploring the Inhibitory Effects of Plant Phytoalexins on Escherichia coli: A Genetic Study of Bacterial Resistance Interactions and Gene Expression Associated with Defense Response

The modulation of resistance-associated gene expression and the emerging correlations between gene expression, biofilm formation, and antibiotic resistance suggest that certain plant phytoalexins, particularly resveratrol, may be promising candidates for treating MDR-EC infections.

Alternative Approaches to Antibiotics: Phage Therapy, Antimicrobial Peptides, and Phytotherapeutics

Antibiotic resistance has emerged as a critical threat to global health, food security, and economic stability due to the overuse of antibiotics in human medicine and livestock production. This review examines the mechanisms of antibiotic action and resistance, clinical and environmental consequences of resistance, and evaluates current alternative strategies to conventional antibiotics. Bacteria develop resistance through enzymatic degradation, target modification, reduced membrane permeability, alternative metabolic pathways, and horizontal gene transfer. The misuse of antibiotics in animal breeding as growth promoters has further accelerated the spread of resistant and multidrug-resistant pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. To address this crisis, the review discusses three major alternatives: phage therapy, antimicrobial peptides (AMPs), and phytochemicals/plant extracts. Phage therapy offers highly specific bacterial lysis with minimal impact on microbiota, though challenges include narrow host range and phage resistance. AMPs exhibit broad-spectrum antimicrobial, antibiofilm, and immunomodulatory activities, with several FDA approved peptides already in clinical use, but limitations include high minimum inhibitory concentrations and potential toxicity. Plant-derived phytochemicals demonstrate antibacterial and efflux pump inhibitory effects and show synergistic potential when combined with antibiotics. The findings suggest that a multifaceted approach combining prudent antibiotic stewardship with investment in phage therapy, AMPs, and plant-based compounds is essential to mitigate resistance and ensure sustainable treatment options. Further in vivo studies and clinical trials are needed to optimize efficacy, safety, and large-scale application of these alternatives.

Phytochemical interventions in bacterial resistance: plant metabolites as next-generation antibacterial agents

The increasing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacterial pathogens poses a critical challenge to global health. In response, plant-derived natural products have emerged as promising candidates for the development of novel antibacterial agents. This review comprehensively evaluates 235 plant-based compounds, including alkaloids, terpenoids, phenolics, lignans, saponins, and glycosides, known for their antibacterial activity. The literature was systematically searched through several academic databases, including PubMed, Scopus, and Web of Science, using relevant keywords such as “plant-derived antibacterial agents,” “phytochemicals,” “MDR bacteria,” “XDR bacteria,” and specific compound classes like “alkaloids,” “terpenoids,” and “phenolics.” The 262 articles were selected based on their relevance to antibacterial activity, resistance mechanisms, and pharmacological data. A combination of inclusion and exclusion criteria was applied, with a focus on peer-reviewed studies published between 2015 and 2025. The primary objective of this study is to explore the antibacterial potential of these phytochemicals against Gram-positive and Gram-negative bacteria, with a particular emphasis on resistant clinical strains. Each compound group is examined for its mechanism of action, minimum inhibitory concentration (MIC), and any reported synergistic effects with conventional antibiotics. Many of the reviewed compounds demonstrated potent antibacterial activity, often with MIC values below 10 μg/mL, and exhibited mechanisms such as membrane disruption, enzyme inhibition, and efflux pump interference. These findings underscore the relevance of plant secondary metabolites in addressing antibiotic resistance and provide a framework for their further development as therapeutic agents. The study encourages the continued exploration of plant biodiversity for sustainable antibacterial drug discovery.