Research Projects

Diabetic foot ulcers (DFUs) are chronic, non-healing wounds arising from peripheral neuropathy, atherosclerotic disease, and foot deformities, often leading to severe infections, tissue damage, and amputations. Affecting 12–25% of diabetics globally, DFUs impose a significant healthcare burden, particularly in India, where diabetes-related complications contribute to over one million deaths annually. Hyperglycemia impairs immunity, fostering an environment for MDR pathogens that exacerbate inflammation, delay healing, and disrupt host immune responses. The critical and complex nature of DFUs underscores the urgent need for innovative, targeted therapeutic strategies to effectively manage these wounds, mitigate amputation risks, and enhance the quality of life for individuals with diabetes. Phage-derived endolysins, often termed "enzybiotics," are gaining recognition as a cutting-edge alternative to conventional antibiotics due to their potent broad-spectrum antipathogenic activity and distinct mechanism of action. Building on this premise, for the management of chronic DFUs, we propose the development of an engineered endolysin fused with the immunomodulatory peptide IDR-1018 with proven wound healing effect. Furtherance to maximize therapeutic efficacy and facilitate translational potential, we aim to formulate an engineered endolysin-loaded liposomal aerosol. This advanced delivery system is anticipated to provide dual advantages: enhanced protein stability and a controlled, targeted release mechanism for improved clinical outcomes. Preliminary work: In continuation of our earlier research project [DST File No: EEQ/2020/000288, dated 25.12.2020], the gene encoding an endolysin protein, PSPaEn, was successfully PCR-amplified, cloned, and overexpressed from Pseudomonas bacteriophage PSPa. Further in vitro therapeutic evaluation of purified PSPaEn revealed significant lytic activity against ESKAPE pathogens, inspiring the idea to engineer it with AMP IDR-1018, a renowned immunomodulatory agent and wound healer, forming the foundation of this proposal. Additionally, in silico analyses corroborated the functional integrity and therapeutic potential of PSPaEn, establishing it as a promising candidate for further clinical evaluation to combat DFU-associated infections effectively. Novelty: For the first of its kind, the identified endolysin is derived from host-specific bacteriophages, exhibiting exceptional broad-spectrum antibacterial activity against MDR and XDR pathogens prevalent in DFUs. By fusing it with the immunomodulatory peptide IDR-1018, the resulting engineered protein enhances immune activation and accelerates wound healing through synergistic antibacterial and host-response mechanisms. Further encapsulation in liposomal aerosols will ensure improved stability, prolonged bioactivity, targeted delivery, establishing a cutting-edge therapeutic strategy to combat persistent infections, and promote effective DFU treatment.