The Deconstructed Granuloma: A Complex High-Throughput Drug Screening Platform for the Discovery of Host-Directed Therapeutics Against Tuberculosis

Frontiers in Cellular and Infection Microbiology
Lu HuangAmanda C Brown

Abstract

Mycobacterium tuberculosis (Mtb) continues to be a threat to Global Public Health, and its control will require an array of therapeutic strategies. It has been appreciated that high-throughput screens using cell-based assays to identify compounds targeting Mtb within macrophages represent a valuable tool for drug discovery. However, the host immune environment, in the form of lymphocytes and cytokines, is completely absent in a chemical screening platform based on infected macrophages alone. The absence of these players unnecessarily limits the breadth of novel host target pathways to be interrogated. In this study, we detail a new drug screening platform based on dissociated murine TB granulomas, named the Deconstructed Granuloma (DGr), that utilizes fluorescent Mtb reporter strains screened in the host immune environment of the infection site. The platform has been used to screen a collection of known drug candidates. Data from a representative 384-well plate containing known anti-bacterial compounds are shown, illustrating the robustness of the screening platform. The novel deconstructed granuloma platform represents an accessible, sensitive and robust high-throughput screen suitable for the inclusive interrogation of immune...Continue Reading

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Citations

Jun 25, 2019·Cellular Microbiology·David G Russell
Sep 11, 2019·Annual Review of Microbiology·Bridget GollanSophie Helaine
Feb 6, 2021·Metabolites·Dorothy Pei Shan Chang, Xue Li Guan
Feb 18, 2020·Drug Discovery Today·Stanislav HuszárVinayak Singh
Apr 3, 2021·Frontiers in Cellular and Infection Microbiology·Hee-Jeong YangLaura E Via
Apr 5, 2021·Cellular Microbiology·Neeraja Subhash, Varadharajan Sundaramurthy
Jul 7, 2021·Antimicrobial Agents and Chemotherapy·Oluwaseun EgbelowoVéronique Dartois

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Methods Mentioned

BETA
flow cytometry
confocal microscopy

Software Mentioned

Prism
DGr
GentleMACS Lung 37C
Volocity
GraphPad
FlowJo
GenScript

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