Chemical-genetic interaction mapping links carbon metabolism and cell wall structure to tuberculosis drug efficacy [preprint]
Proulx, Megan K.
Murphy, Kenan C.
Baker, Richard E.
Shaffer, Scott A.
Sassetti, Christopher M.
UMass Chan AffiliationsMass Spectrometry Facility
Department of Biochemistry and Molecular Pharmacology
Department of Microbiology and Physiological Systems
Bacterial Infections and Mycoses
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AbstractCurrent chemotherapy against Mycobacterium tuberculosis (Mtb), an important human pathogen, requires a multidrug regimen lasting several months. While efforts have been made to optimize therapy by exploiting drug-drug synergies, testing new drug combinations in relevant host environments remains arduous. In particular, host environments profoundly affect the bacterial metabolic state and drug efficacy, limiting the accuracy of predictions based on in vitro assays alone. In this study, we utilize conditional Mtb knockdown mutants of essential genes as an experimentally-tractable surrogate for drug treatment, and probe the relationship between Mtb carbon metabolism and chemical-genetic interactions (CGI). We examined the anti-tubercular drugs isoniazid, rifampicin and moxifloxacin, and found that CGI are differentially responsive to the metabolic state, defining both environment-independent and – dependent synergies. Specifically, growth on the in vivo-relevant carbon source, cholesterol, reduced rifampicin efficacy by altering mycobacterial cell surface lipid composition. We report that a variety of perturbations in cell wall synthesis pathways restore rifampicin efficacy during growth on cholesterol, and that both environment-independent and cholesterol-dependent in vitro CGI could be leveraged to enhance bacterial clearance in the mouse infection model. Our findings present an atlas of novel chemical-genetic-environmental synergies that can be used to optimize drug-drug interactions as well as provide a framework for understanding in vitro correlates of in vivo efficacy.
bioRxiv 2021.04.08.439092; doi: https://doi.org/10.1101/2021.04.08.439092. Link to preprint on bioRxiv.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/29818
This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.
Full author list omitted for brevity. For the full list of authors, see article.