Research Projects

Project Summary: Bacterial resistance to existing antibiotics has emerged as a major global threat, creating an urgent need for the development of new, effective, broad-spectrum antibiotics with novel modes of action. Antimicrobial resistance (AMR) affects individuals of all ages and countries, posing a serious challenge to advancements in medicine and public health. India is among the nations severely affected by drug-resistant pathogens. According to reports, in 2019 alone, more than 10 lakh people in India were infected with drug-resistant bacteria, leading to over 3 lakh deaths. Globally, an estimated 4.95 million deaths were associated with bacterial resistance in 2019. Projections indicate that by 2050, more than 3 million deaths may occur annually in India due to AMR if immediate interventions, including the discovery of new antibiotics, are not undertaken. The World Health Organization (WHO) has highlighted alarming levels of antibacterial resistance in several key pathogens, including Acinetobacter baumannii, Enterobacterales, Salmonella Typhi, Shigella spp., Enterococcus faecium, Pseudomonas aeruginosa, Staphylococcus aureus, Neisseria gonorrhoeae, and Mycobacterium tuberculosis, among others. Infectious diseases continue to be a leading cause of mortality in India and worldwide, further reinforcing the urgent need for novel antibiotics. Recent studies suggest that bacteria find it more difficult to develop resistance against membrane-disrupting agents compared to drugs that target specific intracellular biomolecules. Disrupting the negatively charged bacterial cell membrane through selective drug binding represents a promising strategy to combat pathogenic and drug-resistant bacteria. In this context, cationic host-defense antimicrobial peptides (AMPs), known for their broad-spectrum antimicrobial activity, have gained considerable attention. However, natural AMPs often suffer from poor bioavailability, non-specificity, and high hemolytic activity. In our recent work, we discovered a 15-residue ααγ-hybrid peptide with excellent activity against ESKAPE pathogens and multi-drug-resistant strains, including Acinetobacter baumannii, E. coli, Enterococcus faecium, MRSA, and VRSA. This peptide also exhibited low hemolytic activity and enhanced proteolytic stability (see preliminary results). In this proposal, we aim to explore the therapeutic potential of ααγ-hybrid peptides as next-generation antibiotics. We will synthesize a series of ααγ-hybrid peptides and evaluate their in vitro antibacterial activity against ESKAPE pathogens and their multidrug-resistant variants including MRSA, VRSA and resistant strains. In addition, we will examine the efficacy of the peptides against the WHO-priority strains such as Enterobacterales, Salmonella Typhi, Shigella spp., Enterococcus faecium, and Neisseria gonorrhoeae. Further, we will assess in vivo efficacy of potent αα-hybrid peptides using mouse models. Beyond antibacterial activity, we will investigate their potential to inhibit biofilm formation and suppress the development of bacterial resistance. Additionally, we will explore their antifungal activity against pathogenic fungi such as Candida albicans, Candida auris, Coccidioides, and Histoplasma species. Overall, this project aims to develop novel antibiotics with distinct mechanisms of action. The expected outcomes will have significant implications for public health and could contribute meaningfully to the global fight against AMR.