Bac7-HC1 conjugate significantly enhances intracellular antibacterial activity of α-helical AMPs against bacterial infections

Intracellular bacterial infections pose a significant global health challenge, often leading to treatment failures due to antimicrobial resistance. While antimicrobial peptides (AMPs) offer broad-spectrum activity and address resistance, their efficacy against intracellular pathogens is severely limited by poor cellular uptake. Cell-penetrating peptides (CPPs) are a promising strategy to enhance AMP delivery into cells and improve their intracellular bactericidal activity. However, the diverse nature of CPPs and their varied cellular uptake mechanisms mean the most effective CPPs for AMP delivery remain unidentified, creating a critical gap in therapeutic design.

Researchers conjugated six representative cell-penetrating peptides (CPPs) to the model α-helical antimicrobial peptide HC1. These conjugates were then systematically evaluated for their ability to enhance cellular uptake and demonstrate intracellular antibacterial activity. The assessment included both in vitro assays to measure uptake efficacy and in vivo studies to confirm intracellular bactericidal effects against bacterial infections. The study aimed to identify the most effective CPP for improving AMP delivery and therapeutic performance.

The systematic evaluation revealed that Bac7-HC1, a conjugate of the cell-penetrating peptide Bac7 and the model α-helical AMP HC1, was the most effective candidate.

Bac7-HC1 significantly enhanced both cellular uptake efficacy and intracellular antibacterial activity across in vitro and in vivo models. This superior performance suggests that specific characteristics of CPPs are crucial for optimizing AMP delivery. The findings highlight that cationic or amphipathic CPPs, especially those possessing intrinsic antimicrobial activity and a high positive charge, are particularly effective in boosting the anti-infective performance of HC1-based conjugates. This work identifies Bac7-HC1 as a promising lead candidate for developing new therapeutics against challenging intracellular bacterial infections.