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Updated: May 3, 2026
A High-throughput Compatible Assay to Evaluate Drug Efficacy against Macrophage Passaged Mycobacterium tuberculosis
Published on: March 24, 2017
A metabolic biosignature of early response to anti-tuberculosis treatment
Sebabrata Mahapatra, Ann M Hess, John L Johnson
1Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA. jbelisle@colostate.edu.
Background:
The successful treatment of tuberculosis (TB) requires long-term multidrug chemotherapy. Clinical trials to evaluate new drugs and regimens for TB treatment are protracted due to the slow clearance of Mycobacterium tuberculosis (Mtb) infection and the lack of early biomarkers to predict treatment outcome. Advancements in the field of metabolomics make it possible to identify metabolic profiles that correlate with disease states or successful chemotherapy. However, proof-of-concept of this approach has not been provided for a TB-early treatment response biosignature (TB-ETRB).
Methods:
Urine samples collected at baseline and during treatment from 48 Ugandan and 39 South African HIV-seronegative adults with pulmonary TB were divided into discovery and qualification sets, normalized to creatinine concentration, and analyzed by liquid chromatography-mass spectrometry to identify small molecule molecular features (MFs) in individual patient samples. A biosignature that distinguished baseline and 1 month treatment samples was selected by pairwise t-test using data from two discovery sample sets. Hierarchical clustering and repeated measures analysis were applied to additional sample data to down select molecular features that behaved consistently between the two clinical sites and these were evaluated by logistic regression analysis.
Results:
Analysis of discovery samples identified 45 MFs that significantly changed in abundance at one month of treatment. Down selection using an extended set of discovery samples and qualification samples confirmed 23 MFs that consistently changed in abundance between baseline and 1, 2 and 6 months of therapy, with 12 MFs achieving statistical significance (p < 0.05). Six MFs classified the baseline and 1 month samples with an error rate of 11.8%.
Conclusions:
These results define a urine based TB-early treatment response biosignature (TB-ETRB) applicable to different parts of Africa, and provide proof-of-concept for further evaluation of this technology in monitoring clinical responses to TB therapy.
Insights
Researchers identified a urine-based biosignature for early tuberculosis (TB) treatment response. This discovery, using metabolomics, could speed up clinical trials for new TB drugs and regimens.
Area of Science:
- Metabolomics
- Biomarker Discovery
- Tuberculosis Research
Background:
- Tuberculosis (TB) treatment requires prolonged multidrug chemotherapy.
- Evaluating new TB drugs is hindered by slow infection clearance and lack of early predictive biomarkers.
- Metabolomics offers potential for identifying metabolic profiles linked to disease states and treatment success.
Purpose of the Study:
- To establish proof-of-concept for a TB-early treatment response biosignature (TB-ETRB) using metabolomics.
- To identify a reliable urine-based biosignature for monitoring early TB treatment response.
Main Methods:
- Urine samples from HIV-seronegative pulmonary TB patients in Uganda and South Africa were analyzed using liquid chromatography-mass spectrometry.
- Metabolomic data were processed to identify molecular features (MFs) that changed during treatment.
- Statistical analyses, including t-tests, hierarchical clustering, and logistic regression, were used to select and validate MFs for the biosignature.
Main Results:
- 45 molecular features (MFs) showed significant changes in abundance after one month of TB treatment.
- 23 MFs consistently changed between baseline and multiple treatment time points (1, 2, and 6 months).
- A biosignature of six MFs accurately classified baseline versus 1-month treatment samples with an 11.8% error rate.
Conclusions:
- A urine-based TB-early treatment response biosignature (TB-ETRB) was defined.
- This biosignature is applicable across different African populations.
- The study provides proof-of-concept for using metabolomic biosignatures to monitor TB treatment response.
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