Gates Package — page 1297

'active against TBRU Summary September 20, 2018 Other Research Highlights DRUGS • Development and application of novel mass spectrometry-based profiling technologies with the potential to increase the lesion 'penetrance' of new drug candidates • Used TRIP screens to ID new regulators and effectors of sensitivity to INH. Developed an experimentally-derived in silico approach to predicting drug:drug interactions. • Biphasic efficacy in combination treatment with isoniazid and bedaquiline identified through a biochemical screening, network modeling and machine learning approach. We find that early antagonism is shared with other electron transport chain inhibitors and that late potentiation is explained by collateral sensitivity to bedaquiline resulting from acquisition of isoniazid resistance. • PET/CT could prove a novel means to assess novel preventive therapy regimens in Experimental Medicine studies involving far fewer (2 orders of magnitude) participants than traditional trials of preventive therapy that are largely based in any case on equivalence, not superiority. • Developing novel models of M. tuberculosis persistence to enable better drug-screens that are active against persisting/latent stage bacteria. • Our data inform new approaches to host directed drug therapy including vitamin A supplementation and antihyperglycemic treatment with Metformin and related drugs. • New beta-lactams with improved functional properties. • The first phosphopantetheinyl transferase inhibitors. • Identification of new high-value targets for drug development, including the transcription termination factor Rho, thioredoxin reductase and biotin protein ligase. • Identification of risks in targeting Mtb's respiratory chain for drug development. • Development and application of genetic approaches for drug MOA analyses. • Identification of human genetic defects in TB patients that could lead to the development of new treatments aimed at restoring immunity. As an example, patients with a genetic defect of IFN-γ production, such as those homozygous for the P1104A TYK2 missense variant, may benefit from treatment with recombinant IFN-γ. • Development and application of novel mass spectrometry-based intrabacterial profiling technologies with the potential to increase the efficiency of TB drug development and enable rational engineering of phenotypic antimicrobial activity into chemical compounds in a target- and species-selective manner. • Discovery of novel approaches for development of mechanism-based drug combinations, including the elucidation of treatment shortening activities of pyrazinamide and identification of targets in pyrazinamidesusceptible Mtb. • Studies of Mtb aerobiology with potential for development into novel transmission blocking strategies. DIAGNOSTICS • A primary aim of the project is to develop biosignatures of risk of transition to active tuberculosis. This will allow targeting of interventions such as treatment of "latent" TB infection to those most likely to benefit • Identification of bacterial factors that predict TB relapse is the first step to develop a pre-treatment sputum test that can assign individualized treatment length to each patient, most likely identifying the majority of patients who can be safely treated for 4 months or less without increased relapse risk. • We are working on diagnostic approaches that involve detection of biomarkers of infection and have preliminarily identified altered phospholipids in the blood and urine of acute TB infection. We have developed lipid specific ELISAs based on tuberculosinyl adenosine that show promise in detecting infection in "resistors" and patients with prior or active tuberculosis. • Biologically unbiased discovery and identification of novel urinary small molecule biomarkers of disease and treatment response from primary human samples. • Development of methods that detect ~1 order of magnitude more viable Mtb per mL of patient sputum than standard methods and demonstrate their differential response to initiation of therapy.