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IIDR and Max Planck Researchers Uncover the Loading Mechanism of an Antibacterial Nanomachine

Author: Christy Groves

PhD students Dennis Quentin (left) of the Max Planck Institute for Molecular Physiology and Shehryar Ahmad (right) of the McMaster Institute for Infectious Disease Research investigate interbacterial killing via the type VI secretion system.

Bacteria produce toxins to compete with other organisms. In many species of Gram-negative bacteria, the secretion and delivery of antibacterial effector proteins from one species of bacteria into another is mediated by a complex macromolecular apparatus called the type VI secretion system (T6SS).

The T6SS resembles a microscopic syringe, puncturing the cell walls of competing bacteria and “injecting” them with toxins in an effort to kill them. The mechanism of action for many of these toxins is known; however, the way in which they are loaded onto the T6SS apparatus and how they translocate across the cell envelope once delivered into a target bacterium has long remained enigmatic.

In a recent publication in Nature Microbiology, researchers from the Max Planck Institute for Molecular Physiology and the McMaster Institute for Infectious Disease Research (IIDR) leveraged their combined expertise in biochemistry, genetics and structural biology to investigate these critical first steps of toxin delivery by the T6SS.

IIDR researcher Dr. John Whitney, who co-lead the study, previously identified the Tse6 toxin and its associated chaperone EagT6 as an ideal model for studying toxin delivery by the T6SS. Using samples provided by the Whitney lab, PhD student Dennis Quentin of Dr. Stefan Raunser’s lab at the Max Planck Institute used electron cryomicroscopy to capture snap-shots of the chaperone-bound toxin during different stages of its delivery from an “attacking” bacterium into a target bacterium. This structural work revealed an unprecedented level of molecular detail into the mechanism of T6SS-mediated protein trafficking.

To test hypotheses generated from the cryo-EM structures, IIDR PhD student Shehryar Ahmad used genetic and biochemical approaches to show that the precise role of the EagT6 chaperone is to load the Tse6 toxin onto the T6SS apparatus so that it can be “injected” into a prey bacterium. Though their study focused on a single toxin-chaperone pair, the frequent presence of Eag chaperone encoding genes in T6SS-containing bacteria suggests that these findings will apply to many T6SS-delivered toxins.

By implicating molecular chaperones as crucial components of interbacterial competition, this work gives us greater insight into how bacteria are able to kill and compete with one another, which could help pave the way for the discovery of new antibacterial therapeutics that can ultimately improve human health.

Read the full Nature Microbiology publication here, and Dennis Quentin’s Behind the Paper summary entitled ‘Molecular insights into the frontline of bacterial warfare ‘.


Christy Groves