Exploiting Mycobacterium tuberculosis biofilm-derived phenotypes for transformative novel drug discovery

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Tuberculosis (TB) killed 1.3 million people in 2018. Deaths are predicted to rise in the coming years as COVID has devastated TB control programmes worldwide.TB drug therapies are failing, treatment of drug-sensitive disease takes a combination of 4 drugs for 6 months, and TB accounts for one third of antimicrobial drug resistant (AMR) infections. New drugs are desperately required, however efforts are hampered as we do not understand the physiology of the biofilm-like growth of bacilli in pulmonary lung lesions that are the target of chemotherapy.This project will apply cutting-edge molecular techniques to characterise the sub-populations of Mycobacterium tuberculosis (M.tb) that exist when grown as a biofilm, to mimic the human lung phenotype. The proposal partners expertise in M.tb pathogenesis/transcriptomics (Waddell), bacterial biofilms (Webb), with a long-standing industrial partner at PHE-Porton, expert in drug discovery (Bacon).Objectives and Approaches:Optimise an existing model of mycobacterial biofilm-like growth developed in the Waddell lab (Sussex), with biofilm expertise from Webb (Southampton). Training in microbiology (Sussex), biofilm methodologies (Southampton).Characterise the tb sub-populations that are generated by biofilm- like growth. Measure the impact of phenotypic diversity on drug tolerance. Develop single cell/sub-population level transcriptomics with Dolomite Bio, an established microfluidics company specialising in the encapsulation of cells in droplets for Dropseq applications. Training in molecular biology and bacterial transcriptomics (Sussex).Define the heterogeneity of tb in biofilms using flow cytometry/FACS through a world-leading CL3-FCM facility in the Bacon lab (PHE-Porton). Industry placement(s) at PHE-Porton.Establish a microtitre plate tb biofilm assay to screen for new paradigm-shifting cidal compounds. Training in early drug discovery from all partners and NBIC. The project will develop innovative technologies to understand the fundamental lung biology of M.tb, and the diverse bacterial phenotypes that develop in biofilms, identifying novel drug targets and treatment strategies.