Nothing wasted: Peptidoglycan recycling in mycobacteria

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Mycobacterium tuberculosis is a living paradox. Amongst bacteria, it possesses one of the single most complex and carbon-rich cell walls and yet it thrives in the decidedly nutrient poor environment of the human lung. This is made even more impressive considering the fact that components of the mycobacterial cell wall are potent triggers of the innate immune system. Therefore, to support stable growth in their host, these bacteria must be exquisitely efficient with their available nutrients and be able to hide themselves from the immune system. The innermost component of the mycobacterial cell wall is a complex macromolecule called peptidoglycan (PG). While textbook illustrations of PG suggest that it is a static bag-like structure, in reality it is a heavily modified and dynamic molecule that prevents the cell from exploding while simultaneously giving it shape. Throughout the life cycle of the bacterium, PG must constantly and carefully be cut and remodeled to support growth and division. Researchers have long studied PG, chiefly because of its essential nature. Indeed, the first clinical antibiotic, penicillin, specifically targets the biosynthesis of PG. While much of this biosynthesis has been understood for many years, relatively little is known about what happens to PG after it is built. This is even truer for the PG of M. tuberculosis, which is a global pathogen and the second leading killer of people amongst infectious diseases. For example, nothing is known about the fate of mycobacterial PG fragments once lytic enzymes have cut them from the cell wall. This is an important question because as mentioned above, these PG fragments are potent stimulators of the immune system and command a great deal of scarce resources to make. Intriguingly, these same PG fragments are capable of triggering resuscitation of the bacterium from the dormant phase of its lifestyle. Dormant M. tuberculosis is capable of persisting undetected for years inside of its host before producing an active infection. This severely complicates control of the disease and associated outbreaks, because even if they are detected, dormant M. tuberculosis are exceptionally antibiotic resistant. These points make it clear that an understanding of the fate of M. tuberculosis cell wall fragments is needed. In some bacteria complex PG recycling systems have been described which work by bringing PG fragments back into the cell to be reused. In all cases observed to-date this recycling system is important to the ability of the bacterium to infect its host. Despite this, PG recycling has never been investigated in M. tuberculosis. It is important that this pathway be investigated because it is very likely that the elements of a mycobacterial PG recycling system are novel antibiotic targets. During this Fellowship I will use new and exciting techniques to demonstrate that mycobacteria recycle their PG. I will take a high-resolution approach by exploring the precise structure of the PG fragments that are being recycled. I will then determine the cellular machinery that is required for PG recycling and characterise the key proteins involved in the pathway. Finally, I will examine the relationship between tuberculosis resuscitation and PG recycling. This work will address the M. tuberculosis paradox and show how it is able to balance its nutritional and growth requirements with its nutrient poor environment and the need to hide itself from our immune system.