Research Projects

Bacterial antimicrobial resistance (AMR) is a significant global public health threat, with AMR rising in common pathogens in India. This necessitates continuous efforts for the discovery and development of durable antimicrobials. Antibiotic discovery has been in peril over the last few decades, as antimicrobial candidates with multiple modes of action can exhibit increased potency and thwart bacterial resistance. Existing clinical antibiotics act by a single mode of action, and bacteria have rapidly acquired resistance to all of them. This proposal aims to transform existing uni-targeted antibiotics into dual-targeted antibiotics through rational chemical modifications that impart an additional new mode of action: inhibition of bacterial cell wall lipid recycling. Bactoprenyl-pyrophosphate, a vital component of bacterial cell walls, is disrupted when bactoprenyl-pyrophosphate function is disrupted, leading to impaired cell wall biosynthesis. Zinc-binding metallophores, such as dipicolyl and terpyridyl, have a high affinity towards pyrophosphates, making them ideal targets for antibiotics. Chemical conjugation of zinc-binding metallophores to existing antibiotics would yield antibiotic analogues capable of targeting the pyrophosphates of bacterial cell wall lipids, disrupting peptidoglycan precursor translocation and impaired cell wall biosynthesis. The findings of this proposal will guide the development of better therapeutics, as targeting cell wall lipid recycling with antibiotic classes has not been reported before.