Transcription Regulation: Structure and Mechanism

Resistance to antibiotics represents an escalating challenge in the treatment of bacterial infections. Pseudomonas aeruginosa a gram-negative, opportunistic human pathogen has been recently listed as the "critical" category pathogen in the DBT-WHO priority list. A significant contribution to the persistence of P. aeruginosa is due to its ability to transition from flagellated to biofilm mode of life. These phenotypic transitions are regulated at the level of transcription, which is the pivotal regulatory checkpoint for gene expression in bacteria.

We employ an integrated approach, involving structural tools, biophysical techniques, biochemical methods and functional in vivo assays to investigate the molecular mechanisms of transcription regulation of flagellar and biofilm genes in P. aeruginosa. The mechanistic insights obtained are exploited for the discovery of novel therapeutic agents.

Specific projects

1. Transcription regulation of flagellar gene network in Pseudomonas aeruginosa: P. aeruginosa is an opportunistic human pathogen that is the primary cause of nosocomial infections. It possesses a single polar flagellum which is crucial for motility, attachment to the host, pathogenesis, and biofilm formation.  We aim to understand the regulatory mechanisms governing bacterial flagellar assembly, which is pivotal in unraveling the details of bacterial motility and pathogenesis.

    

2. Targeting transcription factors to mitigate biofilms in Pseudomonas aeruginosa: Pseudomonas aeruginosa causes acute and chronic, hard-to-treat infections. The persistence of P. aeruginosa is due to its ability to develop into biofilms, which are sessile bacterial communities attached to substratum and encapsulated in layers of self-produced exopolysaccharides. The biofilms provide enhanced protection from the host immune system and resilience towards antibiotics which poses a challenge for treatment. Thus, identifying novel targets and understanding the detailed mechanism of biofilm regulation becomes imperative. We use high-throughput in-silico tools for structure-based drug discovery to identify inhibitors of P. aeruginosa biofilms. The hits obtained are validated in-vitro and in-vivo.