Our laboratory studies regulatory networks in Mycobacteria that control intrinsic resistance to a variety of stresses imposed by its environment, including oxidative and genotoxic stress, hypoxia, nutrient starvation, and exposure to multiple antibiotics which are common to both pathogenic and saprophytic species. Although a number of pathways have been described to account for the observed resistances, the mechanisms that control the expression of genes required in these processes remain poorly defined.
The ability of M. tuberculosis, the causative agent of tuberculosis, to persist for many years in its human host, and the requirement for lengthy antibiotic regimens to eliminate drug sensitive strains reflects the effectiveness of the responses to stressful environments, many of which are likely to be adapted from stress responses common to mycobacteria, including saprophytes such as Mycobacterium smegmatis, our model organism. The detailed pathways, signals, regulatory responses and molecular interactions are not yet well understood; however, it is clear that mycobacteria have very effective mechanisms to sense the environment and translate these into adaptive responses involving global transcriptional reprogramming. This presumably involves complex and overlapping regulatory pathways reflected in the M. tuberculosis proteome of about 190 transcription regulators including sigma (ï3) factors, two component systems, protein kinases as well as over a hundred transcription activators and repressors. Understanding these regulatory circuits is therefore critical in the understanding of mycobacterial persistence and drug resistance.
We have identified a “master” regulatory network in M. smegmatis that controls the expression of a regulon required for resistance to genotoxic agent mitomycin C, hydrogen peroxide (H2O2) and at least three different antibiotics - isoniazid, chloramphenicol and tetracycline. We are characterizing this network in M. smegmatis and investigating parallel networks in M. tuberculosis using a combination of biochemistry, genetics and genomic approaches.