ISMB Extra Seminar: Friday 22nd November

The talk is entitled "Adapt or die: combining high-throughput biology and live-cell imaging to elucidate cellular and genetic function in mycobacteria"

Understanding cellular and genetic function in Mycobacterium tuberculosis is critical to the development of new therapeutic approaches for tuberculosis (TB), currently the leading cause of mortality owing to a single infectious agent and source of one-third of all antimicrobial resistant (AMR) deaths. Here, two examples will be presented illustrating the use of different microscopy techniques to elucidate both pathway-specific and genome-scale functions involved in the mycobacterial response to lethal stress. The first centres on a mutagenic DNA repair system that has been implicated in DNA damage-induced drug resistance and host adaptation in M. tuberculosis. Applying a panel of fluorescently tagged translational reporters, we reveal the subcellular recruitment and localization of components of this mycobacterial mutasome. Moreover, through the use of the natural product antibiotic, griselimycin, we demonstrate the potential to disrupt mutasome function, in turn supporting the development of “anti-evolution” compounds designed to protect existing and new TB drugs against emergent drug resistance.

In the second example, we harness CRISPR interference and quantitative, image-based analyses to construct and characterize an arrayed library of essential gene knockdown mutants in the related non-pathogen, M. smegmatis. Applying automated imaging and analysis tools, we derive robust quantitative descriptions of bacterial morphologies, providing an atlas of morphological changes consequent on essential gene-depletion in mycobacteria. Leveraging statistical-learning approaches, we demonstrate that functionally related genes cluster based on morphological similarity, and show that bacterial morphology can be used to suggest hypothetical gene function and to infer drug mechanism-of-action. Our results support the application of large-scale image-based analyses to essential gene function in mycobacteria, and suggest the utility of this approach for the identification of novel targets that might potentiate existing anti-TB agents.

Venue: Gavin de Beer lecture theatre G04, UCL Anatomy Building, Gower Street, London, WC1E 6BT

All are welcome.