# Evolutionary and Functional Significance of Novel Mutations in MDR-XDR TB

> **NIH NIH R01** · SAN DIEGO STATE UNIVERSITY · 2020 · $670,704

## Abstract

In 2015, there were 10.4 million cases of active tuberculosis (TB) and 1.4 million deaths due to
TB. While we have effective TB treatment, the incidence of drug resistant cases is increasing and
threatens TB control efforts. In 2015, 480,000 new cases of multi drug-resistant TB (MDR-TB)
were reported. Among these, nearly 60,000 were extensively drug-resistant TB (XDR-TB). The
scenario is much worse in some regions. In Belarus, close to one of each two cases (48%) are
MDR-TB (35.3% in new and 76.5% in previously treated TB-patients). Since the global cure rate
of MDR-TB is still well below the target set by WHO for 2015 (exceedingly low in many parts of
the world), and since XDR-TB treatment success rates are even lower (20% in Belarus), there is
an urgent need for improved understanding of the problem and to identify/evaluate new
drugs/combinations of drugs as the situation in Belarus is likely to spread.
Two trials for combinatorial treatment involving four new and repurposed drugs bedaquiline,
linezolid, clofazimine, and delamanid are underway thanks to funding from the World Health
Organization and the Global Fund. As part of these two trials, monthly sputum samples will be
collected for six months from all patients. Unfortunately, in the first trial with 30 patients
having completed the combinatorial treatment, in six the treatment has failed, and one death
has been recorded. This project aims to leverage the resources created by the two trials in order
to uncover previously unknown mechanisms of drug resistance, evolutionary path to resistance,
and timeline to resistance to the four new/repurposed drugs. Our approach will be to use in
silico comparative genomic and epigenetic (methylome and transcriptomic) analysis in order to
curate a comprehensive catalog of uncharacterized (epi)genomic changes in failed treatment
cases. In silico functional characterization of genes and regulatory elements associated with
resistance to the five study drugs will then elucidate the mechanism of resistance. A subsequent
phylogenomic analysis and MIC characterization of time-course samples will allow us to
understand the evolutionary path to resistance, and the change in resistance level after each
evolutionary event. This will allow us to understand for example whether resistance emerges in
steps with increasing levels, or spontaneously at a high level. In the case of the former, we will be
able to identify the stepwise genetic and methylation markers associated with each resistance
level. This allows the clinician to decide whether increasing the drug dosage or change of the
drug regimen is the best course of action.

## Key facts

- **NIH application ID:** 9980263
- **Project number:** 5R01AI105185-07
- **Recipient organization:** SAN DIEGO STATE UNIVERSITY
- **Principal Investigator:** Faramarz Valafar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $670,704
- **Award type:** 5
- **Project period:** 2013-07-19 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980263

## Citation

> US National Institutes of Health, RePORTER application 9980263, Evolutionary and Functional Significance of Novel Mutations in MDR-XDR TB (5R01AI105185-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980263. Licensed CC0.

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