# BEYOND BURDEN: NEW TOOLS FOR TUBERCULOSIS ANTIBIOTICREGIMEN DESIGN

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2023 · $194,375

## Abstract

Project Summary
A key priority for combatting the global tuberculosis (TB) epidemic is shortening the length of treatment required
to reliably cure TB. A critical impediment to drug and regimen development is the lack of metrics of effective
treatment response for use in drug discovery and pre-clinical development. Two factors considered crucial to
shortening treatment are the capacity of a drug to penetrate and accumulate in lung lesions and the inherent
activity of a drug against residual drug-tolerant Mycobacterium tuberculosis (Mtb) populations that survive initial
drug killing. This proposal focuses on the inherent treatment-shortening activity of drugs, independent of PK.
Unfortunately, the bacteriological basis of why existing TB drugs and regimens vary in treatment-shortening
activity remains unclear. This project evaluates the basis of drug treatment-shortening activity in TB, focusing
particularly on the role of overall bacterial activity and replication during treatment. Conventionally, drugs are
assessed based on the degree to which they lower Mtb burden. Our alternative approach evaluates how drugs
affect fundamental bacterial cellular processes. Specifically, we developed an assay that quantifies how drugs
affect ongoing ribosomal RNA synthesis called RS ratio. We found TB drugs and regimens that shorten treatment
profoundly suppress rRNA synthesis; whereas drugs with high bactericidal activity but low treatment-shortening
activity allow surviving Mtb populations to sustain rRNA synthesis. The RS ratio is already transforming drug
development pipelines and clinical trials, but the physiological basis for the predictive power of the RS ratio
needs to be fully elucidated. Since the rate of rRNA synthesis is fundamentally correlated with replication rate,
we hypothesize that Mtb replication during treatment is an important unrecognized factor in treatment-shortening.
Aim 1 will elucidate the effect of diverse drugs on replication while validating the RS ratio as a measure of Mtb
replication and establishing a series of confirmatory molecular assays. Aim 2 will test the paradigm in vivo by
evaluating pairwise combinations selected based on their potency on inhibiting Mtb replication. Collectively, our
innovations are moving beyond crude measures of bacterial burden to a new era in which drugs and regimens
are evaluated based on nuanced multifaceted molecular testing of their impact on fundamental physiologic
processes of the pathogen.

## Key facts

- **NIH application ID:** 10667002
- **Project number:** 1R21AI171065-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** MARTIN Inua VOSKUIL
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $194,375
- **Award type:** 1
- **Project period:** 2023-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10667002

## Citation

> US National Institutes of Health, RePORTER application 10667002, BEYOND BURDEN: NEW TOOLS FOR TUBERCULOSIS ANTIBIOTICREGIMEN DESIGN (1R21AI171065-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10667002. Licensed CC0.

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