Optimized TPL6 Peptide Gel Exhibits Broad-Spectrum Antimicrobial Activity and Effectively Treats Drug-Resistant Wound
Wen-Chun Lin1, Ming-Feng You1, Yun-Ru Chen2
1Marine Research Station, Institute of Cellular and Organismic Biology, Academia Sinica, Jiaushi, Ilan, Taiwan.
Abstract:
Antibiotics are the primary treatments for diabetic foot infections (DFIs) but are often ineffective against severe, polymicrobial, or drug-resistant microbial strains. Antimicrobial peptides (AMPs) offer broad-spectrum activity, yet most fail in clinical translation due to known limitations. Here, TPL6 is developed, a TP4-derived AMP with glycine-rich segments deleted, yielding a variant with potent, robust antimicrobial activity and reduced cytotoxicity. TPL6 retains its α-helical structure and activity under high glucose and salt, and after heat stress. It also does not induce microbial resistance after prolonged exposure. Formulated with adjuvants into a hydrogel, TPL6 gel restores activity in serum-rich environments and outperforms Bacineocin ointment in simulated wound fluid. The gel further prevents formation and eradicates biofilms of multidrug-resistant (MDR) pathogens. In ex vivo porcine skin and diabetic mouse wound models infected with MDR Staphylococcus aureus or Candida albicans, TPL6 gel shows superior therapeutic efficacy versus Bacineocin ointment and Canesten 1% cream. Thus, this study shows that structural modification and adjuvant-based formulation of TPL6 can overcome key translational barriers that have hindered clinical application of AMPs, supporting its potential as an antibiotic-free treatment for drug-resistant wound infections.
Insights
A novel antimicrobial peptide, TPL6, shows potent activity against drug-resistant microbes causing diabetic foot infections. Formulated in a hydrogel, TPL6 effectively treats wounds, offering a promising antibiotic-free alternative.
Area of Science:
- Biochemistry
- Microbiology
- Biomaterials Science
Background:
- Diabetic foot infections (DFIs) pose a significant challenge due to antibiotic resistance.
- Antimicrobial peptides (AMPs) show promise but face clinical translation hurdles.
- Existing treatments often fail against severe, polymicrobial, or drug-resistant infections.
Purpose of the Study:
- To develop and evaluate TPL6, a modified antimicrobial peptide, as a potential treatment for DFIs.
- To assess TPL6's stability, resistance to microbial adaptation, and efficacy in preclinical models.
- To investigate the therapeutic potential of TPL6 formulated in a hydrogel for wound healing.
Main Methods:
- Structural modification of TP4-derived AMP to create TPL6, deleting glycine-rich segments.
- Assessment of TPL6's antimicrobial activity, cytotoxicity, and stability under various stress conditions (high glucose, salt, heat).
- Formulation of TPL6 into a hydrogel with adjuvants and evaluation in simulated wound fluid, ex vivo skin, and in vivo diabetic mouse models.
Main Results:
- TPL6 demonstrated potent antimicrobial activity and reduced cytotoxicity compared to parent AMP.
- TPL6 maintained structural integrity and activity under stress and did not induce microbial resistance.
- TPL6 hydrogel effectively prevented and eradicated biofilms of multidrug-resistant pathogens.
- TPL6 gel exhibited superior therapeutic efficacy in ex vivo and in vivo models compared to conventional treatments.
Conclusions:
- Structural modification and adjuvant-based hydrogel formulation overcome key translational barriers for AMPs.
- TPL6 represents a promising antibiotic-free therapeutic candidate for drug-resistant wound infections.
- This approach supports the clinical application of AMPs for challenging infections like DFIs.
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