Towards a molecular, mechanistic, understanding of bacterial type three secretion

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Secretion of proteins into the environment is a fundamental feature of bacterial life. This mechanism allows pathogenic bacteria to cause disease both by secretion of toxins and also by assembling the secreted proteins to form the nano-machines required for motility. Many important human pathogens use type 3 secretion systems, T3SS for short, to perform these functions with deletion of the T3SS rendering the bacteria non-pathogenic. The T3SS is particularly important for eight of the twelve bacterial families highlighted by the World Health Organisation as those for which we critically need to develop novel antibiotics due to their world-wide disease burden. T3SSs assemble a large nano-machine and work arising from our earlier Programme Grant has recently determined the structure of the gate that controls secretion and lies at its core. This structure has revealed an unexpected location for the gate within the assembled machine that now requires significant redrawing of our previous hypotheses about how T3SS function. This structural information forms the basis for experiments to understand how T3SSs operate. In particular we want to understand how the nano-machine operates to push the cargo out of the bacteria, though the oily membrane that defines the organism. This process requires energy, but it is currently completely opaque how that energy is used to achieve export of precisely the right proteins. By determining molecular structures we hope to be able to gain insight into this critical process by understanding how the molecules involved are arranged and re-arranged to achieve the export step. This work has the potential to aid the design of drugs to attack pathogenic bacterial families by providing information about molecular detail of the mechanics of this nano-machine that may suggest novel routes to break the system using drug-like molecules.