Research Projects

Bacterial machineries for cell wall biosynthesis including both the associated enzymes and precursor molecules are widely used as potential target for the development of novel antimicrobial drugs. Among the precursor molecules the most promising target is the Lipid II, a highly conserved unit across the bacterial world comprising disaccharide-pentapeptide subunits linked to a polyisoprenoid anchor via a pyrophosphate linker. Intriguingly, the efficacy of the antimicrobial agents is dependent on which part of lipid II is targeted by the antibiotics. Being a polycyclic antimicrobial peptide Nisin shows remarkable efficacy against various gram positive bacteria due to strong intermolecular hydrogen bonding with the pyrophosphate moiety of lipid II. The highly conserved structure of lipid II resists any structural modification and emerges as a promising target for designing effective antimicrobial agents to overcome the common problem of drug resistance. However, the facile degradation of Nisin by protease enzyme and high cost of production leads to limited clinical success. Further, majority of the lipid II targeting antibiotics reported till date including most prospective Nisin are specific to gram positive bacteria as unable to penetrate the outer membrane of gram negative bacteria due to large size. Considering all these limitations of lipid II targeting antibiotics reported so far, small molecule antibiotics targeting pyrophosphate moiety of lipid II would be an important strategy to prevent bacterial resistance, enhanced efficacy, and low production cost. Therefore, aim of this project is to develop novel small molecule antibiotics targeting the pyrophosphate moiety of lipid II. Here, rational design of amine and amide based small molecule library containing either 1,3- diphenyl or thiophene ring as the core structure has been achieved. The reason behind choosing such molecules is the involvement of both amine as well as amide groups in intermolecular hydrogen bonding with the pyrophosphate moiety. In addition, it is envisaging that the hydrophobic core structure of the designed molecules might be anchored with the lipid bilayer of plasma membrane, which will facilitate intermolecular hydrogen bonding between amine/amide functional group with the pyrophosphate unit. Based upon their antimicrobial efficacy screening of the libraries to sort out lead small molecules will be done along with evaluation of biocompatibility of the same. Lead molecules with satisfactory biocompatibility will be monitored in vitro for binding ability with lipid II pyrophosphate and permeabilizing the outer cell membrane using various biophysical as well as biochemical assays and finally antimicrobial efficacy will be evaluated in rodent model.