Antibiotic resistance is a global public health issue, accelerated by the misuse and overuse of antibiotics. Microenvironment-targeted antimicrobial delivery is an emergent and promising strategy for selective antibiotic delivery that targets the site of infections and may reduce drug resistance. The local pH of infected tissues can be a primary target for designing materials with pH-triggered antimicrobial activity. Given the urgent need to combat bacterial infections in diseases with an elevated pH, we report on the design and synthesis of a new alkaline-responsive antimicrobial hydrogel. The gels are based on a polydiacetylene-peptide (PDA-Pep) having pH-dependent molecular and macromolecular structure and packing. Upon pH elevation, the peptide domain is deprotonated and triggers the conformational change of the PDA domain, leading to a colorimetric transition from blue to purple. Simultaneously, the deprotonation induces a gel-to-sol macroscopic phase transition of the fiber network formed in PDA-Pep hydrogels, which causes the selective release of the antimicrobial agents that are encapsulated in the gels into the infection site to kill bacteria. The translational potential of PDA-Pep hydrogels for pH-sensing and on-demand alkaline-triggered antibiotic delivery was demonstrated on inoculated pig skins. The work lays the foundation for the development of multifunctional alkaline-responsive materials in which multiple small molecule or macromolecular therapeutics can be encapsulated to achieve synergistic biological functions against a wide range of multidrug-resistant pathogens.
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