# Identification of gene targets that potentiate the action of rifampicin on Mycobacterium bovis BCG

## TL;DR

This study identifies genes in Mycobacterium bovis BCG that make the bacteria more sensitive to the antibiotic rifampicin, potentially helping to improve TB treatments.

## Contribution

The study uses TnSeq to discover new gene targets that enhance the effectiveness of rifampicin against mycobacteria.

## Key findings

- Mutants with enhanced sensitivity to rifampicin were identified in genes related to DNA/RNA metabolism, cellular regulation, and cell wall synthesis.
- A dose response was observed for rifampicin sensitivity in selected mutants.
- The dataset provides insights into mechanisms of mycobacterial tolerance and adaptive responses to rifampicin.

## Abstract

Tuberculosis (TB) caused by bacteria of the Mycobacterium tuberculosis complex remains one of the most important infectious diseases of mankind. Rifampicin is a first line drug used in multi-drug treatment of TB, however, the necessary duration of treatment with these drugs is long and development of resistance is an increasing impediment to treatment programmes. As a result, there is a requirement for research and development of new TB drugs, which can form the basis of new drug combinations, either due to their own anti-mycobacterial activity or by augmenting the activity of existing drugs such as rifampicin. This study describes a TnSeq analysis to identify mutants with enhanced sensitivity to sub-minimum inhibitory concentrations (MIC) of rifampicin. The rifampicin-sensitive mutants were disrupted in genes of a variety of functions and the majority fitted into three thematic groups: firstly, genes that were involved in DNA/RNA metabolism, secondly, genes involved in sensing and regulating mycobacterial cellular systems, and thirdly, genes involved in the synthesis and maintenance of the cell wall. Selection at two concentrations of rifampicin (1/250 and 1/62 MIC) demonstrated a dose response for mutants with statistically significant sensitivity to rifampicin. The dataset reveals mechanisms of how mycobacteria are innately tolerant to and initiate an adaptive response to rifampicin; providing putative targets for the development of adjunctive therapies that potentiate the action of rifampicin.