The Mycobacterium tuberculosis Cell Envelope: unravelling complex cell wall assembly, degradation and re-cycling pathways

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Tuberculosis (TB) is a bacterial infection caused by the tubercle bacillus. Worldwide TB remains the leading bacterial cause of mortality and morbidity. In 2016, the WHO reported 10.4 million new cases of TB, with 1.7 million people dying from TB that year. Predominantly a disease of poverty, TB affects young adults in their productive years and hence also carries a large economic burden. This picture is highlighted by populations living in low and middle income countries (LMICs), where the burden of TB is most prevalent, with high morbidity and mortality rates, such as in India (510,000 p.a.), Indonesia (130,000 p.a.), China (38,000 p.a.), Nigeria (240,000 p.a.) and South Africa (97,000 p.a.). Therefore, introducing a new TB drug onto the market and its impact upon the health and global economy for these LMICs represents an urgent healthcare challenge, which needs to be viewed on at least a 10-15-year timescale. Our application seeks support for research into the cell envelope of Mycobacterium tuberculosis. All bacterial cells are enclosed in a cell wall or cell envelope. This is a dense layer of covalently-linked molecules around the cellular membrane, protecting the organism from its immediate environment. The cell wall of M. tuberculosis is very distinctive, differing from other bacteria in containing an exceptional amount of unique lipids (fats) and sugars. This high content of lipids and sugars makes the M. tuberculosis cell wall impermeable to most antibiotics. At the same time, the organism is very vulnerable if the cell wall has defects. Therefore, some existing TB antibiotics interfere with the synthesis of cell wall components, and for the same reason many TB drug development efforts focus on the cell wall. Our research will concentrate on learning more about the biology surrounding the M. tuberculosis cell wall. Firstly, building on our previous studies on lipid synthesis, we will examine enzyme systems that degrade lipids. This is important because M. tuberculosis has limited access to nutrients and has developed strategies to recycle molecular components for new uses. Secondly, we will study how M. tuberculosis assembles sugar-like polymers, such as arabinogalactan and the key virulence factor, lipoarabinomannan, outside of its cell membrane. Our third aim is to understand a range of enzymes that appear to play a role in remodelling peptidoglycan, a molecular 'mesh' that is commonly found in bacteria, but has distinct features in M. tuberculosis. Fourthly, we will use small-scale mechanical probes to clarify how the bacteria are constructed and help explain how interactions of the key building blocks influence virulence. In characterising the enzymes and proteins involved in these biological processes, we aim to find proteins that are 'good' drug targets, for instance because they are unique to this organism or because the cell cannot compensate when they are inactivated by a drug. To achieve this goal, our research will rest on three fundamental research pillars: 1) the identification of essential mycobacterial proteins and how the interaction between the protein target and an inhibitor can be improved; 2) determine how and why these compounds kill bacilli, their mode of action; and 3) develop our partnerships with laboratories in LMICs, such as the Institute of Materia Medica (IMM), Beijing, China and the Indian Institute of Science (IISc), Bangalore, India, and through our industrial links with GlaxoSmithKline Diseases of the Developing World (GSK DDW), Madrid, Spain, develop drug discovery projects to turns 'hits' into 'leads' and ultimately into new TB-drugs. Thus, this proposal offers the opportunity to tackle a range of fundamental questions about an organism that has puzzled microbiologists ever since its discovery by Robert Koch in 1882, that can be used to treat a debilitating disease which represents one of the most pressing healthcare challenges for Society in the 21st Century.