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 genetics and bacterial genetics/genomics, we hope to provide insight into possible new paradigms for addressing infectious diseases.
Despite recent, largely genetic, technical advances in the field of in vivo pathogen-host interactions, many important questions related to the mechanisms of bacterial pathogenesis remain unanswered, in part because of the inability of in vitro conditions to accurately mimic in vivo ones.The newly developing field of chemical genetics offers a novel and promising approach to studying these mechanisms, thus complementing traditional genetic studies. Chemical genetics uses small, organic molecules as specific tools to conditionally induce a phenotype by activating or inhibiting specific protein targets, thus allowing the manipulation of relevant pathways in vitro and in vivo, on very short time scales.
In concert with taking a chemical biological approach to pathogenesis, our lab is interested in developing powerful genomic approaches to facilitate rapid identification of targeted pathways and interactions. Using small molecules that we identify and develop from high-throughput, forward genetic screens to study Vibrio cholerae, Pseudomonas aeruginosa and Mycobacterium tuberculosis, we hope to identify new approaches to disease intervention.
Three areas are of particular interest:
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 have developed 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.
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.
Methodology development for applying chemical biology to bacterial systems
We are interested in developing methods to advance the field of chemical biology, particularly within the context of microbiology. This will involve using genomics and proteomics to facilitate small molecule target identification and the application of small molecules methods to studying in vivo infection.