Linking Peptides and PNAs: Bioorthogonal Nitrile-Aminothiol Conjugation for Antimicrobial Applications

Peptide-peptide nucleic acid (PNA) conjugates targeting essential bacterial genes represent a promising avenue for the development of innovative antisense antimicrobials. Research efforts in this domain have predominantly focused on the identification of novel PNA targets and the optimization of peptide sequences to facilitate the delivery of peptide-PNA conjugates. Importantly, the choice of linkage chemistry for conjugating peptides with PNAs is critical for ensuring efficient delivery and functionality. This study introduces a novel nitrile-aminothiol conjugation strategy for PNA synthesis. The PNA targeting the acyl carrier protein gene (acpP), when conjugated to membrane-active antimicrobial peptides such as polymyxins, demonstrated enhanced antimicrobial efficacy against multidrug-resistant Gram-negative Acinetobacter baumannii. These findings underscore the utility of nitrile-aminothiol conjugation as an effective approach for coupling PNAs with antimicrobial peptides or small molecules, thereby advancing the potential of PNA-based therapeutic strategies.