We are applying gene circuit mapping technologies to comprehend the mechanisms of virulence and antibiotic tolerance in pathogens.

This work includes:
- Mapping of gene circuits in Pseudomonas aeruginosa, a pathogen that chronically infects the lungs of Cystic Fibrosis patients
- Defining the regulatory circuits controlling bacterial persistence and drug tolerance
- Predicting the mode of action of drugs and toxins via analysis of gene expression data

Antibiotic resistance is an ongoing problem because antibiotic use itself leads to the development and spread of resistance through natural selection. The occurance of multi-drug resistant bacteria is increasing, including organisms resisistant to all classes of antibiotics. Even for a new drug, resistance often appears within a few years after its introduction. The development of new antibiotics is an immediate and constant need.

Antibiotic resistance can emerge through mutations in a drug's target protein, through the activation of stress-response mechanisms that protect the cell against drugs, and other mechanisms. Yet even in resistant organisms, the activity of an antibiotic is not usually eliminated, it is only decreased. This presents an opportunity to identify compounds that synergize with existing drugs and restore antibiotic activity to therapeutically useful levels. We are using our knowledge of bacterial stress response pathways gleaned from microarray studies and our network analysis algorithms, to identify gene targets that increase drug susceptibility and slow the emergence of resistance.