An estimated 422 million people worldwide live with diabetes. One in five patients with diabetes will develop a diabetic foot wound (DFW) for which they will require hospitalization. DFWs often become chronic due to complications of uncontrolled diabetes, including nerve damage, compromised immune response and lowered blood flow to the extremities. Infected DFWs are treated by removal of infected tissue and intravenous antibiotics against the infecting pathogens such as Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. However, the underlying complications may result in antibiotic treatment failure related to the ability of infecting bacteria to form adherent communities (biofilms) and develop antibiotic resistance. At least one in five patients hospitalized with a DFW will require amputation. There is therefore and unmet clinical need for novel, anti-infective platforms for infected DFWs which this proposal will advance.
Through a collaboration between medicinal chemists and clinical microbiologists, we will design, synthesise and evaluate pre-clinically, a new class of anti-infectives with potential to effectively deliver enhanced properties to treat and heal infected DFWs. Preliminary data from our laboratory indicates that a number of candidate biocompatible star-shaped peptide polymers kill bacteria that infect DFWs. Our aim is to develop these polymers with enhanced antibacterial action by loading of the antimicrobial polymer scaffolds with microbicidal carbon monoxide (CO)-generating photosensitizing units. These novel platforms will facilitate local delivery of targetted selective antimicrobial activity of the star-shaped antimicrobial polymers and additional controlled delivery of CO in reponse to applied light. The enhanced properties of CO in this setting will deliver anti-biofilm, anti-inflammatory and wound-healing properties to the DFW. Preclinical evaluation of these platforms will include; optimising the light-activated regulated release of CO, confirmation of low toxicity to human cells and investigation of anti-inflammatory, anti-biofilm and wound–healing properties and effective therapeutic concentrations.
