Project: The role of Mycobacterium tuberculosis compensatory mutations in metabolic fitness via the structure and function of mycolic acids

Acronym InformaTB (Reference Number: TMA2017CDF-1885)
Duration 01/12/2018 - 30/11/2021
Project Topic Drug-resistant tuberculosis (TB) remains a world-wide crisis. Despite early work indicating that drug-resistant Mycobacterium tuberculosis is less fit than its drug-susceptible counterparts, M. tuberculosis that is resistant to increasing numbers of drugs continue to emerge and spread. It has been shown that compensatory mutations exist that may explain the ability of the resistant bacilli to retain fitness. Mutations in the inhA promoter are wellknown to cause resistance to at least two drugs. These mutations have been suggested to be a gateway to extensively drug-resistant TB (XDR-TB, resistant to at least 4 key drugs). We propose that, in addition to causing resistance, inhA promoter mutations act as compensatory mechanisms, overcoming negative effects of drug-resistance. We will test this hypothesis by targeted mutagenesis and fitness assays. In particular, inhA promoter mutations cause the upregulation of two genes involved in mycolic acid synthesis (mabA and inhA), as well as one gene involved in haem biosynthesis (hemZ). We aim to show that this upregulation causes an increase in the amount of mycolic acids synthesised, which in turn increases the functionality of mycolic acids. We will show that this function is to facilitate the sequestration of ferrous iron, nitric oxide or oxygen by isolation of mycolic acids and measurement of the concentration of these molecules in a solution containing mycolic acids. This fellowship will allow the candidate to plan and carry out the proposed work, leading to longer-term projects that will emanate from the results generated during this project, including investigation of further structurefunction relationships of different mycolic acids, as well as the related role of haem in the utilization of reactive oxygen or -nitrogen species. Building out the project will increase opportunities for postgraduate student supervision, as well as international collaborations and publications. This work focuses on an important drug-resistance mechanism, and will aid in elucidating additional functions of this mechanism. This will contribute to a better understanding of the physiology of the bacillus and may lead to novel insights for drug design.
Network EDCTP2
Call Career Development Fellowships 2017

Project partner

Number Name Role Country
1 Stellenbosch University Coordinator South Africa