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A Multistress Model for High Throughput Screening Against Nonreplicating Mycobacterium tuberculosis

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Mycobacteria Protocols

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2314))

Abstract

Models of nonreplication help us understand the biology of persistent Mycobacterium tuberculosis. High throughput screening (HTS) against nonreplicating M. tuberculosis may lead to identification of tool compounds that affect pathways on which bacterial survival depends in such states and to development of drugs that can overcome phenotypic resistance to conventional antimycobacterial agents, which are mostly active against replicating M. tuberculosis. We describe a multistress model of nonreplication that mimics some of the microenvironmental conditions that M. tuberculosis faces in the host as adapted for HTS. The model includes acidic pH, mild hypoxia, a flux of nitric oxide, and other reactive nitrogen intermediates arising from nitrite at low pH and low concentrations of a fatty acid (butyrate) as a carbon source.

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Acknowledgements

We are very grateful for the numerous contributions toward the development of the nonreplicating assay and critical reading of this chapter: Julia Roberts, Yan Ling, Selin Somersan-Karakaya, Landys Lopez-Quezada, David Little, Maneesh Pingle, Kristin Burns-Huang (Weill Cornell Medical College, NY, USA) and Alfonso Mendoza-Losana, Maria Martinez-Hoyos, and Manuel Marin-Amieva (GSK, Tres Cantos, Spain). This work was supported by the TB Drug Accelerator Program of the Bill and Melinda Gates Foundation and by the Abby and Howard P. Milstein Program in Translational Medicine. The Department of Microbiology and Immunology was supported by the William Randolph Hearst Foundation.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA

    Ben Gold & Carl Nathan

  2. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Thulasi Warrier

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  1. Ben Gold
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  2. Thulasi Warrier
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  3. Carl Nathan
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Correspondence to Ben Gold .

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Editors and Affiliations

  1. Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, USA

    Tanya Parish

  2. Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, USA

    Anuradha Kumar

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Gold, B., Warrier, T., Nathan, C. (2021). A Multistress Model for High Throughput Screening Against Nonreplicating Mycobacterium tuberculosis . In: Parish, T., Kumar, A. (eds) Mycobacteria Protocols. Methods in Molecular Biology, vol 2314. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1460-0_27

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  • DOI: https://doi.org/10.1007/978-1-0716-1460-0_27

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