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With the emergence of new pathogens and the increasing antibiotic resistance of old pathogens, novel ways of thinking about therapeutics and for combating infectious diseases must be developed. The goal of my research is to understand in vivo mechanisms of bacterial pathogenesis by studying pathogen-host interactions. By merging the powerful fields of chemical biology and bacterial genetics/genomics, we hope to provide insight into possible new paradigms for addressing infectious diseases. Using small molecules that we identify and develop from high-throughput, forward chemical genetic screens to study Vibrio cholerae, Pseudomonas aeruginosa and Mycobacterium tuberculosis, we are probing in vivo phenotypes of the pathogens and determining new approaches to intervening on pathogenicity.

Two areas are of particular interest during in vivo infection:

1. Virulence expression and regulation – We are interested in identifying genes that are essential only in vivo during infection and in understanding the regulation of these genes. Why are these genes turned on in the host and what are the signals that trigger their expression? We are currently studying in vivo virulence regulation of V. cholerae (cholera toxin and the toxin co-regulated pilus) in an infant mouse model of cholera and have identified potential signals that initiate virulence expression in the host gut.

We are also developing a P. aeruginosa-zebrafish model of infection in order to examine bacterial determinants of infection using both chemical biological and genetic/genomic approaches. The model will allow us to identify not only genes that are essential for P. aeruginosa survival in the host and that are required for virulence, but also host factors that mediate immune responses to infection.

2. Latency and persistence - Critical challenges to treating infections such as TB include the issues of latency and its associated drug tolerance. A similar phenomenon exists for bacteria such as P. aeruginosa in biofilms. Traditional approaches have failed to characterize this state of in vivo latency. Using chemical and traditional genetic approaches, we are trying to understand what defines this state and determines bacterial commitment to latency, as well as to find ways out of latency.

Last Update: 8/22/2013

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© 2013 by the President and Fellows of Harvard College