With the emergence of new pathogens and the increasing antibiotic resistance of old pathogens, novel ways of thinking about therapeutics for combating infectious diseases must be developed. The goal of the Hung lab's 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, Hung and her colleagues hope to provide insight into possible new paradigms for addressing infectious diseases. Using small molecules identified and developed from high-throughput, forward chemical genetic screens to study Vibrio cholerae, Pseudomonas aeruginosa, and Mycobacterium tuberculosis, the Hung laboratory is 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 – Hung and her colleagues 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? The lab is 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 has identified potential signals that initiate virulence expression in the host gut.
Hung and her colleagues 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 them 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. Drug tolerance, resistance, latency and persistence – Critical challenges to treating infections such as TB include the issues of genotypic drug resistance and phenotypic drug tolerance. The molecular mechanisms by which bacteria are able to adapt and survive the stresses of chemotherapy are largely unknown. The Hung lab is interested in understanding the mechanisms by which mutations are engendered that result in genotypic resistance and mechanisms by which bacteria adopt a physiologic state that is associated with phenotypic drug tolerance in the absence of resistance-conferring mutations. Using chemical and traditional genetic approaches, the Hung lab is trying to understand what defines these states and determines bacterial commitment to drug tolerance and latency.