The research sheds light on specific protein interactions that could provide new treatment strategies to combat cholera

The research sheds light on specific protein interactions that could provide new treatment strategies to combat cholera

Bacterial infectious diseases still contribute heavily to the global burden of disease, and with increasing antibiotic resistance worldwide, there is an urgent need for novel treatment strategies against bacteria. One of the most devastating bacterial infections is cholera, caused by the bacterium Vibrio cholerae, which is experiencing its seventh sustained pandemic since 1961. Now a research group led by Osaka University in Japan has shed light on a specific protein interaction that causes the potential to be a new target in cholera treatment.

Cholera is characterized by severe diarrhea, which in worst cases can be fatal within hours. One of the most important steps in the infection process of V. cholerae is that the bacterium colonizes the human intestine by secreting a colonization factor called TcpF, although the exact mechanism behind this secretion remained unclear. Now, in a study soon to be published in Science Advances, researchers used X-ray crystallography, physicochemical analysis and structural modeling to reveal exactly how V. cholerae secretes TcpF.

“The toxin-coregulated pilus (TCP), a type 4 pilus system, was known to play a crucial role in TcpF secretion, but the exact interaction between the two was unclear,” explains Hiroya Oki, lead author of the study. Pili are filament-like structures on the surface of bacterial cells that can have a variety of functions. The TCP of V. cholerae is composed primarily of numerous TcpA subunits, with an initial minor subunit consisting of a TcpB trimer attached to the “top” of the pilus to facilitate its assembly. The group studied the interaction of TcpF with TcpA and B and built models based on the results.

We observed that TcpF trimerized into a flower-like unit to bind to the TcpB trimer at the end of the pilus.”

Shota Nakamura, senior author of the study

Importantly, we identified separate conserved domains that are critical for TcpF binding to TcpB and TcpF trimerization, both of which are required for V. cholerae colonization.

Considering their results in the context of other published work, the group hypothesized that a secretion model exists in which TCP transports TcpB-bound TcpF out of the cell, whereupon TcpF dissociates from the pilus and moves freely in the human intestine, initiating the early stages of V. cholerae colonization. TCP then retreats back into the bacterial cell to repeat the process.

Given the growing resistance to antibiotics, findings such as these, which clarify the molecular details of an infection, can be of great value for the development of new antibacterial drugs. The development of an antiadhesive agent that selectively inhibits the interaction between TcpF colonization factor and the TCP secretion system may represent a novel treatment strategy to combat cholera.

Source:

Osaka University

Reference:

Oki, H., et al. (2022) Structural basis for the toxin-coregulated pilus-dependent secretion of the colonization factor Vibrio cholerae. Scientific advances. doi.org/10.1126/sciadv.abo3013.

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