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

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.

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.

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.

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.