# Mycobacterium tuberculosis precursor rRNA as a measure of treatment-shortening activity of drugs and regimens

## TL;DR

This paper introduces a new way to measure how well TB drugs shorten treatment by looking at ribosomal RNA synthesis in the bacteria.

## Contribution

The study introduces precursor rRNA as a novel biomarker to assess treatment-shortening activity of TB drugs.

## Key findings

- Sterilizing drugs significantly suppress M. tuberculosis precursor rRNA synthesis.
- The rRNA synthesis ratio correlates with treatment shortening in multiple models.
- Non-sterilizing drugs have minimal impact on rRNA synthesis.

## Abstract

There is urgent need for new drug regimens that more rapidly cure tuberculosis (TB). Existing TB drugs and regimens vary in treatment-shortening activity, but the molecular basis of these differences is unclear, and no existing assay directly quantifies the ability of a drug or regimen to shorten treatment. Here, we show that drugs historically classified as sterilizing and non-sterilizing have distinct impacts on a fundamental aspect of Mycobacterium tuberculosis physiology: ribosomal RNA (rRNA) synthesis. In culture, in mice, and in human studies, measurement of precursor rRNA reveals that sterilizing drugs and highly effective drug regimens profoundly suppress M. tuberculosis rRNA synthesis, whereas non-sterilizing drugs and weaker regimens do not. The rRNA synthesis ratio provides a readout of drug effect that is orthogonal to traditional measures of bacterial burden. We propose that this metric of drug activity may accelerate the development of shorter TB regimens.

It is unclear why different antibiotics vary in their ability to shorten treatment of tuberculosis. Here, the authors show that a measure based on ribosomal RNA synthesis in Mycobacterium tuberculosis correlates with treatment shortening in culture, in mice and in human studies.