Molecular characterisation of antibiotic tolerance in Mycobacterium tuberculosis

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, killed 1.8 million people in 2016 which is more than any other single pathogen. It is one of the leading causes of death by a curable disease worldwide. However, unlike most bacterial infections, the treatment for TB involves taking hundreds of pills for at least six months and up to two years. One of the reasons it takes so long to cure TB is the effects of antibiotic tolerance. Anti-TB antibiotics kill most, but not all, of the bacteria and it takes a very long time to eradicate the few ‘tolerant’ bacteria. Understanding how mycobacteria become tolerant to antibiotics will allow us to develop treatments that may be able to cure TB much more rapidly. We have recently shown that one of the mechanisms that cause tolerance in TB is that mycobacteria make frequent mistakes when making new proteins – termed mistranslation.

We propose to find out precisely how mycobacteria control the mistranslation rate. We will also use genetic screens to identify other mechanisms that cause tolerance in TB from samples taken from patients and in a mouse model of the disease.