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Gene expression responses to anti-tuberculous drugs in a whole blood model

Philip Kam Weng Kwan1, Wenwei Lin1, Ahmad Nazri Mohamed Naim2

  • 1Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block Level 10, 1E Kent Ridge Road, Singapore, 119228, Singapore.

BMC Microbiology
|April 9, 2020
PubMed
Abstract

Insights

Transcriptional responses in whole blood bactericidal activity (WBA) assays closely mirror tuberculosis (TB) patient responses in vivo. This transcriptomic approach can help evaluate new TB drugs and reveal their mechanisms of action.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Pharmacology

Background:

  • There is a critical need for improved tools to assess novel or repurposed drugs for tuberculosis (TB).
  • The whole blood bactericidal activity (WBA) assay is a promising candidate for evaluating TB drug efficacy.
  • This study investigates the utility of WBA assays in reflecting in vivo TB responses and elucidating drug mechanisms.

Purpose of the Study:

  • To determine if transcriptional responses in the whole blood bactericidal activity (WBA) assay align with tuberculosis (TB) responses observed in patients.
  • To explore the potential of the WBA assay, augmented with transcriptomics, to uncover mechanisms of action for TB drugs.
  • To assess the WBA assay's capability in differentiating the effects of individual TB drugs.

Main Methods:

  • Analysis of gene expression profiles from whole blood cultures treated with standard TB drug combinations and individual agents.
  • Comparison of gene expression data from WBA assays with sputum gene expression data from TB patients undergoing treatment.
  • Utilizing transcriptomics to identify distinct molecular pathways associated with different drug exposures.

Main Results:

  • A significant overlap (79%) was observed between differentially expressed genes in WBA assays and those found in sputum of TB patients treated with a standard drug combination.
  • Gene expression profiles in WBA assays clustered according to individual drug exposure, including novel combinations.
  • Distinct molecular pathways were identified for individual drugs, with isoniazid's pathways correlating with known mechanisms.

Conclusions:

  • The WBA assay demonstrates substantial agreement with in vivo TB patient responses, supporting its use in drug evaluation.
  • Transcriptomic analysis of WBA assays can differentiate the effects of individual drugs, offering insights into their mechanisms.
  • Integrating transcriptomics with WBA assays holds significant potential for advancing the evaluation of new and repurposed TB drugs.
Keywords:
Anti-tuberculosis drugsFaropenemGene expressionMechanism of actionMicroarrayTranscriptomeTuberculosisWhole blood assay

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