Tuberculosis is one of the leading causes of death in the world, killing about 1-2 million people per year. Mycobacterium tuberculosis bacilli are only known to naturally infect humans. Although healthy individuals usually control M. tuberculosis growth, immunosuppression due to a variety of causes can result in increased bacterial replication and the onset of symptoms. Antibiotic therapy is prolonged and the failure to comply with treatment can lead to the development of multi-drug and extensively drug resistant strains. New drugs to treat tuberculosis are urgently needed, thus we are working to identify activities in M. tuberculosis that could be targeted.
A pathway that is essential for the successful pathogenesis of M. tuberculosis is protein degradation by a proteasome.
We study the mechanics of proteasomal degradation as well as the pathways regulated by degradation that promote the successful pathogenesis of M. tuberculosis in humans. We use biochemistry, genetics, and animal infection models to understand how
M. tuberculosis became one of the most successful pathogens on the planet.
Regulation of Proteasomal Degradation
Dozens if not hundreds of different proteins are degraded by a proteasome system in mycobacteria. While several key components of proteasomal degradation have been identified, we do not know how degradation is activated. Additionally, while most known proteasome substrates are post-translationally modified with a small protein called Pup (prokaryotic ubiquitin-like protein), it is not yet understood how these proteins are selected for "pupylation". We are using genetic and biochemical approaches to characterize the regulation of these processes in M. tuberculosis.
Artwork by Ashley Szendiuch
Cytokinin Signaling in Bacteria
Prior to our work, hormones called cytokinins were only known to stimulate transcriptional changes in plants. Our research revealed that M. tuberculosis produces and senses cytokinins for reasons we are working to understand. Importantly, other bacterial genera produce cytokinins for reasons that also remain to be determined.
Arabidopsis thaliana grown by Marie Samanovic-Golden with
the Coruzzi lab.
M. tuberculosis, which is only naturally found in humans, encodes numerous proteins that counteract the potentially toxic effects of copper. These observations suggest the maintenance of copper homeostasis is critical during human infections. We are interested in understanding how copper kills M. tuberculosis and the pathways that modulate bacterial copper levels.
In collaboration with Sarah Stanley and Russell Vance at UC Berkeley, Sarah Dunstan at University of Melbourne, and Eric Kool at Stanford, we are testing the hypothesis that metabolic aldehydes can be used to control infections. Along these lines, we are working to understand how M. tuberculosis responds to various aldehydes, an activity that may be required for virulence.
Artwork by Kyle Gabler