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Tuberculosis (TB) is responsible for 1.4 million deaths annually, making the causative agent, Mycobacterium tuberculosis (Mtb), the deadliest bacterial pathogen worldwide. The challenge in combating TB is the absence of an effective vaccine and the emergence of extensive drug-resistance. To come up with urgently needed new concepts for new anti-TB therapeutics and prophylactics, a better understanding of how pathogenic mycobacteria function on a molecular level is essential. Mycobacteria have a unique and extremely hydrophobic cell envelope, consisting of two membranes. This complex structure serves as an efficient permeability barrier, essential for pathogenic mycobacteria to survive during infection, and also conferring intrinsic resistance to most antibiotics. While seemingly impenetrable, these bacteria use a set of type VII secretion systems (T7SSs) for the export of extracellular proteins that mediate crucial interactions with the host. We study how T7SSs are able to transport proteins across the mycobacterial cell envelope, while maintaining the integrity of this protective layer. Our latest achievement is the first high-resolution structure of a full T7SS membrane complex from Mtb. The structure describes a large 2.32 MDa assembly with an astonishing number of 165 transmembrane domains and a closed central secretion conduit. We are currently building on this knowledge to obtain a deeper understanding of substrate recognition by and subsequent transport through the elucidated membrane conduit. Elucidating T7SSs, as the “weak spots” of the impermeable mycobacterial cell envelope, will inspire new strategies for anti-TB treatments.

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