Peptide Nucleic Acids (PNAs) in Antimicrobial Therapy: A Next Generation Strategy.

The global rise in antimicrobial resistance (AMR) demands innovative strategies beyond traditional antibiotics. Peptide Nucleic Acids (PNAs), synthetic DNA analogues with peptide-like backbones, act as thermically, chemically, and enzymatically stable sequence-specific agents capable of silencing essential bacterial genes. Through antisense mechanisms, PNAs bind bacterial mRNA or rRNA, blocking translation or ribosome assembly and thereby inducing species-specific growth inhibition. Their programmable design enables precise targeting of multidrug-resistant pathogens while sparing commensal microbiota. Recent advances, including γ-modified backbones, cationic substitutions, and delivery platforms such as cell-penetrating peptides (CPPs), dendron conjugates, and nanoparticles, have improved solubility, stability, and cellular uptake. Studies show promising in vitro and, albeit less frequently, in vivo efficacy against both Gram-positive and Gram-negative bacteria, often with synergistic activity when combined with conventional antibiotics. Although challenges remain in delivery and large-scale production, PNAs represent a promising class of antimicrobials to combat AMR through targeted gene inhibition.