Identification of gene targets that potentiate the action of rifampicin on mycobacteria

Tuberculosis (TB) caused by bacteria of the Mycobacterium tuberculosis complex remains one of the most important infectious diseases of mankind. Isoniazid (INH) and rifampicin are the main first line drugs used in multi-drug treatment of TB. However, the necessary duration of treatment with these drugs is impractically long and development of resistance against these compounds and other TB drugs is an increasing impediment to treatment programs. 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 INH and rifampicin. This project described a TnSeq analysis to identify mutants with enhanced sensitivity to a sub-minimum inhibitory concentration level of rifampicin. The putatively 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 that were transporters and potentially regulating the export of drugs from the mycobacterial cell and lastly a group of genes that were identified as transcriptional regulators and kinases and have the ability to regulate the cellular systems in the mycobacteria. The gene-set includes several genes with established connections to drug/rifampicin sensitivity, thus validating the selection.