Research Projects

Antimicrobial resistance (AMR) poses a critical challenges in the 21st century worldwide, contributing to 4.95 million deaths in 2019, and is expected to escalate in the coming years. A recent study by the Global Research on Antimicrobial Resistance reports that, in India alone, 33 % of the sepsis deaths are linked to AMR. The median reported rates in 76 countries of 42% for third-generation cephalosporin-resistant E. coli and 35% for methicillin-resistant S. aureus are a major concern. Traditional strategies such as stewardship, infection control and vaccination have not been sufficient for treating AMR threats. The small molecule antibiotics do not offer long-term solution owing to the inevitable evolution of resistance. Moreover, easy clearance and poor bioavailability leads to limited penetration ability in the hard-to-treat biofilms. An urgent need, therefore, calls for the development of alternate technologies that can efficiently work against a broad spectrum of AMR. In the context of alternative antibacterials, different strategies include antibacterial peptides, metal nanoparticles, bacteriophages and host-directed therapy. Antibacterial peptides impact natural immune response, while bacteriophages target specific bacterial cells. Metal nanoparticles are known to generate ROS and disrupt the bacterial membrane. Despite their promises, they face barriers like immunogenic response, instability, specificity and large-scale production. Moreover, such agents fail in biofilm-based enhanced resistant infections. Considering these challenges, nitric oxide (NO), a short-lived, diatomic, lipophilic gas, provides a robust strategy and alternative to conventional drugs, displaying a broad-spectrum antimicrobial character. NO acts by inducing oxidative stress in bacteria, primarily causing DNA damage. NO is also known to promote healing by stimulating angiogenesis and collagen synthesis. These multifunctional properties have motivated researchers to develop NO delivery systems to harness the antimicrobial properties and use them for tissue regeneration and repair. However, the traditional NO delivery systems are restricted by burst release, poor solubility, untargeted delivery, poor stability in serum, and non-enzymatic action. Vesicular systems with appropriate size and encapsulation efficiency likely provides a useful system for targeted delivery, similar to extracellular vesicles. Therefore, we ask a critical question: can an efficient vesicular catalyst be developed for targeted NO delivery to eradicate broad-spectrum AMR with improved therapeutic outcome? We aim to answer this question by introducing a metallo-vesicular system, MetaV, capable of exhibiting oxidase enzyme-like activity. Coordination-driven self-assembly using “lego-like” building block makes MetaV a modular supramolecular structure, with varying functions from each part. The active metal center of MetaV catalytically generates NO from endogenous substrates S-nitrosothiols/nitrites under physiological conditions through a redox cycling of the copper center in presence of biological reducing agent GSH or photochemically. The vesicular structure of MetaV scaffold would allow efficient delivery to the target site with reduced clearance, in contrast to archetypal small molecule-based approaches. The proven stability and cytocompatibility of the MetaV will minimize systemic toxicity while killing both planktonic and biofilm-associated pathogens. Further, the healing properties of NO will accelerate tissue repair and support faster wound healing. Moreover, we aim to incorporate the MetaV system with the bio-adhesive hydrogels to generate an injectable formulation that will show prolonged residence at the infected site to promote antibacterial efficacy and accelerated wound healing. The proposed strategy would establish an effective platform for combating antibacterial resistance and host tissue healing, using chemical innovation in metallo-supramolecular assembly.