Closing the gap Tailoring peptides and hydrogel platforms for infected wound treatment

Chronic wounds are susceptible to bacterial colonization and biofilm formation and are often characterized by persistent inflammation and impaired tissue repair. The increasing prevalence of multidrug-resistant (MDR) infections further complicates their treatment and highlights the need for alternative therapeutic strategies. Antimicrobial peptides (AMPs) are promising candidates because of their rapid, broad-spectrum antimicrobial activity and low propensity for resistance development. However, their therapeutic application is limited by reduced activity and stability in the wound environment. This thesis aimed to advance AMP-based treatment of infected wounds by addressing these limitations through peptide discovery, optimization, and localized delivery.
Novel AMPs with potent activity against clinically relevant MDR pathogens were identified using a machine learning-guided approach, demonstrating the potential of computational methods to accelerate AMP discovery. Modification of AMP structure further showed that peptide properties can be tailored to improve antimicrobial and wound healing activity. To overcome the limitations of applying free peptides to wounds, AMP-functionalized hydrogel wound dressings were developed to provide localized antimicrobial activity while supporting wound healing. These platforms enabled effective AMP delivery against clinically relevant pathogens and provided opportunities to combine antimicrobial treatment with modulation of the wound environment. In particular, incorporation of AMP, SAAP-148 together with the anti-inflammatory drug celecoxib improved bacterial clearance and modulated inflammatory responses in an in vivo infected wound model.
Overall, this thesis demonstrates that combining AMP discovery and optimization with localized hydrogel-based delivery can enhance the therapeutic potential of AMPs and provides a foundation for multifunctional, locally acting antimicrobial therapies for complex infected wounds.