Grant: Operating Grant

Mycobacterium tuberculosis (Mtb) is the causative agent of Tuberculosis (TB) which is still a major worldwide problem with current figures showing one third of the world's population infected, 8 to 9 million new cases of active TB and over 2 million deaths due to TB every year. Current vaccines and chemotherapeutic measures are limited in their efficacy and are failing to prevent the spread of disease. Although the present multi-drug schedule of treatment has the potential to cure more than 80% of cases, it lasts at least 6 months and requires that several drugs are taken in the right combinations. Because of this, many patients do not actually receive full and effective treatment. This inappropriate treatment has led to the emergence of multi-drug resistant TB (resistant to two or more of the primary anti-TB drugs) and extensive-drug resistant TB (MDR plus resistance to any fluoroquinolone, and resistance to at least one second-line injectable drug). This is reflected in the fact that up to 2% of patients cannot be cured with today's cocktail of drugs. In addition to acquired resistance to drugs due to genetic mutations, there appears to be an element of intrinsic resistance to antibiotics in Mtb and also non-inherited antibiotic tolerance amongst a sub-population of the bacteria within the host. These latter bacteria are in a distinct physiological state known as persistence or dormancy. It is these persisters that are hard to eradicate leading to the lengthy treatment regimen that in turn leads to poor compliance and the emergence of genetic drug resistance. Our proposal aims to obtain a better understanding of intrinsic resistance and the phenotypic drug tolerance in persister populations of Mtb. Our findings will facilitate the discovery of new therapeutics for the treatment of TB.