Mycobacteria are a diverse family of bacteria that includes the pathogens that cause the specific diseases tuberculosis, Hansen’s disease (leprosy) and Buruli Ulcer. Other environmental mycobacteria cause opportunistic infections in soft tissues, lungs and skin and are an omnipresent threat to long term cystic fibrosis management. The treatment of mycobacterial disease is made challenging by the progressive increase in drug resistant strains, innate drug tolerance and resistance mechanisms including latency, and drug inaccessibility posed by a thick waxy cell envelope and growth in granulomas or biofilms. The drug regimens for mycobacteria usually require a cocktail of antimicrobials administered over a long period of time and may not eradicate the pathogen, even those that are susceptible to the administered drug. New and more effective treatments are urgently needed. Gaining a deeper understanding of what makes populations of mycobacteria so successful and resilient may present new possibilities.

We develop, adapt and refine molecular biology tools that allow us to explore mycobacterial genomes with greater sensitivity and precision than ever before. We combine multiple genome-wide tools, such as whole-genome sequencing, transcription profiling, translation initiation and ChIP-seq approaches to more fully understand the products and the regulation of gene expression. We find that mycobacteria often differ from conventional bacterial models, leading us to amend prevailing dogma on occasion. Examples include the prevalence of leaderless translation initiation, hundreds of undocumented small proteins that are actively produced, and an attenuation network that controls the expression of amino acid biosynthetic genes that is the most extensive in any bacterium. We exploit the fast-growing and non-pathogenic Mycobacterium smegmatis as a proven mycobacterial model organism to develop and test new ideas before validation in less tractable mycobacteria.

Bacterial isolates evolve by surviving and growing in hostile and competitive niches, whether environmental or host. Cells in an expanding population will contact sibling (kin) cells in addition to other microbes or host cells. Kin or non-kin contact will likely elicit different responses that are relevant and beneficial to that contact. Such contact-dependent activities may be missed in traditional reductive monoculture studies. We use a form of direct horizontal gene transfer called distributive conjugal transfer (DCT) as a model of cell-cell interactions between mycobacteria. DCT assays quantify the transconjugant end-products of two distinct conjugative strains of M. smegmatis. Our studies are revealing a signal transduction pathway that begins with non-kin cell-cell contact and includes two secretion systems and other supporting activities that are activated by contact and required for DCT. We observe many non-DCT contact-dependent gene expression changes that indicate additional higher-order activities are induced and important to surviving non-kin contact. Many of the genes that we have identified in the DCT contact response have virulence functions in pathogenic mycobacteria. Our work is writing the rules of engagement for cell-contact in mycobacterial populations. We believe that this frontier will lead to the elusive deeper understanding needed to catalyze a next generation of effective anti-mycobacterial therapies.

To learn more, please visit the Derbyshire and Gray Laboratory_[1].