Bacterial infectious illnesses continue to be a significant contribution to the global disease burden, and with antibiotic resistance on the rise globally, there is an urgent need for innovative antibacterial treatment options. Cholera, caused by the bacterium Vibrio cholerae, is one of the most lethal bacterial illnesses and has been in its sixth pandemic since 1961. Now, a Japanese research team led by Osaka University has shed light on a unique protein interaction that might be a fresh target in Cholera treatment.
Cholera causes severe diarrhea, which can be lethal within hours at its worst. The bacteria colonizes the human gut by secreting a colonization factor termed TcpF, which is one of the most crucial phases in the infection process of V. cholerae, albeit the specific mechanism behincolonized its secretion remains unknown. Researchers employed X-ray crystallography, physicochemical investigations, and structural modeling to explain exactly how V. cholerae secretes TcpF in a work that will be published shortly in Science Advances.
According to Hiroya Oki, the study's primary author, it was known that the Toxin-coregulated pilus (TCP), a type 4 pilus system, played an important role in TcpF secretion, but the specific connection between the two was unknown.
Pili are filament-like structures found on the surface of bacterial cells that serve a variety of purposes. The V. cholerae TCP is predominantly made up of TcpA subunits, with an initial small component consisting of a TcpB trimer attached to the top of the pilus to aid in assembly. The team investigated the interaction of TcpF with TcpA and B and developed models based on the findings.
According to the study's principal author, Shota Nakamura, "we observed that TcpF trimerized into a flower-like unit to bind to the TcpB trimer at the end of the pilus." We discovered two conserved domains that are essential for TcpF binding to TcpB and TcpF trimerization, both of which are required for V. cholerae colonization.
In light of these findings, the researchers proposed a model of secretion through which TCP transports TcpB-bound TcpF out of the cell, following which TcpF dissociates from the pilus and travels freely in the human gut, commencing the early phases of V. cholerae colonization. TCP then retracts back into the bacterial cell to begin the process all over again. Given the rise in antibiotic resistance, discoveries like these that provide light on the molecular aspects of infection can be extremely useful in the development of new antibacterial medications. The discovery of an anti-adhesive drug that selectively inhibits the interaction of the TcpF colonization factor and the TCP secretion system may give a unique therapeutic option for Cholera.
The article Structural basis for the toxin-coregulated pilus-dependent secretion of Vibrio cholera colonization factor will be published in Science Advances.
Journal Information: Hiroya Oki et al, Structural basis for the toxin-coregulated pilus–dependent secretion of Vibrio cholerae colonization factor, Science Advances (2022). DOI: 10.1126/sciadv.abo3013. www.science.org/doi/10.1126/sciadv.abo3013
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