A Novel Antimicrobial Peptide Displaying Broad-Spectrum Activity Against Pan-Resistant Pathogens and Low Propensity for Resistance Development

Objectives: The escalation of multidrug-resistant (MDR) clinically relevant bacterial isolates, including Escherichia coli and key ESKAPE pathogens, represents a critical global healthcare threat. While antimicrobial peptides (AMPs) offer promising alternatives, metabolic instability often limits their clinical use. This study investigated the therapeutic potential, antimicrobial efficacy, and resistance dynamics of peptide D-TN6 against highly resistant bacterial strains. Methods: D-TN6 efficacy was evaluated against 164 clinical isolates, including pan-drug-resistant, carbapenem-resistant, and polymyxin-resistant phenotypes. A 20-passage serial induction assay compared resistance development kinetics of D-TN6 against gentamicin over an extended period. Results: D-TN6 demonstrated potent efficacy against MRSA (minimum inhibitory concentration (MIC)90: 1 µg/mL) and remained effective against polymyxin B-resistant Klebsiella pneumoniae (MIC90: 8 µg/mL) and pan-drug-resistant Acinetobacter baumannii (MIC90: 8 µg/mL). In resistance assays, while the gentamicin MIC increased 256-fold by the 17th passage, the D-TN6 MIC remained constant at 1 µg/mL throughout the 20-passage study. Conclusions: These findings underscore D-TN6 as a robust therapeutic candidate. Its efficacy against MDR strains and its feature of low propensity for resistance development—likely due to membrane disruption—position D-TN6 as a promising solution for life-threatening infections where conventional last-resort agents fail.