TConditional ermination of Transcription in Mycobacterium tuberculosis

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Antimicrobial resistance (AMR) is an increasing problem pertaining to all bacterial infections, including tuberculosis (TB), caused by infection with Mycobacterium tuberculosis. According to the latest WHO estimates, drug resistant TB lead to around 240 000 deaths in 2016. Unlike most other pathogens, M. tuberculosis does not rely on plasmid-borne resistance. Instead, M. tuberculosis expresses several natural drug resistance machines called efflux pumps, which excrete anti-bacterial drugs that enter the cell. Transcription is the process of copying DNA to RNA, which is subsequently decoded to synthesise proteins. One way of controlling gene expression is by premature termination of transcription, i.e. the process of transcription is initiated but not completed, meaning there is no RNA to decode and hence no protein is expressed. However, premature termination of transcription can be regulated by physical or molecular signals, in which case it is referred to as conditional termination.Recently, several efflux pumps were shown to be regulated by conditional termination in Bacillus subtilis, Enterococcus faecalis and Listeria monocytogenes, and similar mechanisms are likely to be widespread in other bacteria including M. tuberculosis.The aim of this project is to apply very recently developed methods based on Next-generation sequencing to (1) define the abundance of conditional terminators in M. tuberculosis, and (2) determine to what extent natural resistance mechanisms in M. tuberculosis are controlled by such conditional terminators and (3) to what extent anti-TB drugs control overall gene expression in M. tuberculosis.The successful completion of this project will shed light on regulatory aspects of M. tuberculosis's natural drug resistance, and further our understanding of how anti-TB drugs may contribute to and possibly enhance this drug resistance.