Keith M. Derbyshire
Mycobacterium tuberculosis is a leading cause of death by an infectious agent. It is estimated that one-third of the world’s population is infected with M. tuberculosis and that 1.6 million people die of tuberculosis every year. Its deadly synergistic association with HIV, and the appearance of MDR and XDR strains, exacerbate the global health problems associated with the disease. A comprehensive understanding of the biology of this organism is critical for the identification of novel drug targets, for the development of vaccines, and for determining how it evades the host immune system. This requires the development of basic molecular techniques to determine the genetic and biochemical basis of pathogenesis and drug resistance. To this end, the laboratory utilizes both basic molecular genetic techniques and state-of-the-art genome-wide approaches to determine the genetic architecture, expression and functions of mycobacterial genes.
The focus of Dr. Derbyshire's laboratory is the process of conjugal DNA transfer, which results in the lateral transfer of DNA between bacterial species, and is primarily responsible for the spread of genes encoding virulence and antibiotic resistance. We have identified a novel DNA transfer system in the non-pathogenic, model organism Mycobacterium smegmatis that we call distributive conjugal transfer (DCT) as the transconjugants genomes are a mosaic blend of the parental genomes. The goals of the laboratory are to characterize the mechanism of DCT and to determine its role in the biology of mycobacteria. Notably, a 30-kilobase genetic locus in M. smegmatis is essential for DNA transfer, and encodes a secretory apparatus called ESX-1. This secretion system is highly conserved among mycobacteria and, most relevantly, ESX-1 mutants of M. tuberculosis are attenuated. Thus, by using molecular genetic approaches we can elucidate the mechanism of ESX-1 secretion, and determine its role in both DCT and M. tuberculosis virulence.