Associated organisationsLondon School of Hygiene & Tropical Medicine · Newcastle University · University of Birmingham · The University of MelbourneEurope PMC affiliations are not treated as award recipients or mapped locations.
Funding£5.5M
PeriodMay 2023 — Apr 2031
In plain English
AI plain-English summary
Mycobacterium tuberculosis uses a newly discovered family of enzymes to carve up its own cell wall, reshaping its surface after the wall is built. For decades, researchers have studied how these bacteria assemble their protective outer layers, but almost no one has looked at how they take those layers apart. This team has found that the enzymes—called D-arabinanases—do three distinct jobs: routine maintenance, attacking rival bacteria, and altering how the host immune system responds. The researchers now need to work out exactly what each enzyme cuts, when it gets switched on, and how those cuts help the bacterium survive inside a human lung. This is fundamental science. There is no immediate diagnostic or drug here. But the cell envelope is the frontline of every interaction between mycobacteria and their environment—including the human immune system. Understanding how bacteria deliberately remodel that surface could eventually reveal new weak points for drugs, or explain why some strains evade detection. Similar work on bacterial cell-wall enzymes has, in the past, led directly to antibiotics such as penicillin.
View original technical description
The mycobacterial cell envelope is a complex structure critical for interactions with the host and other bacteria. An important class of cell wall molecules are the D-arabinan containing polysaccharides arabinogalactan and lipoarabinomannan. Decades of research has focused on the biosynthesis of these molecules, with little understanding of how bacteria modify or degrade these structures post-synthesis. We recently discovered a new family of enzymes with endo-D-arabinanase activity and we provide evidence that these enzymes fall into three functional classes: cell maintenance, inter-bacterial competition, and immune modulation. The diversity of functions ascribed to these enzymes underscores the importance of their activity to mycobacterial biology, and yet we know almost nothing about their specificity, how they are regulated, how they contribute to cell fitness or how they enable survival in the host. Our research team has been assembled to draw on crucial expertise to address these questions using cutting-edge approaches and technologies. Together this research program will provide a transformative view of mycobacterial cell surface variation, and revolutionise our understanding of mycobacterial interactions with other bacteria and host cells. It could also lead to new diagnostics, therapeutics or vaccines against mycobacterial diseases such as tuberculosis.
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