Tuberculosis bacteria are the deadliest pathogens worldwide. According to the World Health Organization (WHO), they end more than 1.5 million lives each year and are becoming increasingly resistant to antibiotics. Researchers in Vienna have developed a new active substance against the bacilli (TB), which makes them almost destroy themselves.
This is “two-headed cyclomarin A”, which shreds vital proteins in the bacillus, while malformed products take over. A team led by Tim Clausen at the Research Institute for Molecular Pathology (IMP) in Vienna first investigated how conventional cyclomarin A – an active ingredient from marine microbes – works in tuberculosis bacteria. The point of attack is a shredder made up of six “ClpC1” components in the bacteria. They form a channel at the end of which proteins are chopped.
Normally, only proteins that are incorrectly formed or whose activity is no longer needed enter there, and are therefore harmful to the cells. Cyclomarin A resembles broken proteins and is therefore bound to ClpC1, Clausen explains to the APA. It activates the shredder, but is not drawn into the channel itself. Rather, intact proteins vital to the bacteria end up there.
Bacteria have a defense mechanism
The tuberculosis bacilli naturally have a defense mechanism that protects ClpC1 against overload when many misfolded proteins are present in the cell in extreme situations. Namely in the form of the protein ClpC2, which keeps them away from the shredder. It can also bind cyclomarin A and thus protect ClpC1 against it, the Viennese researchers report in the journal Cell.
Clausen and IMP colleagues have now produced a “two-headed” cyclomarin A. The scientist reported that it binds the six-part ClpC1 shredder channel on one side and a loose ClpC1 component on the other. As a result, the shredder shreds its own parts.
Important proteins are shredded
At some point, it will no longer be possible to assemble enough shredders to take care of misfolded cellular proteins, the researcher said: “That kills the cells.” ClpC1 and its shredding activities are essential for the tuberculosis bacteria to survive.
The two-headed cyclomarine A also traps ClpC2, initiating its degradation. Then ClpC1 can neither be protected against overload by misfolded proteins nor against the active substance. “The two-headed cyclomarin A molecules are extremely efficient because they destroy not only ClpC1, but also this safety mechanism,” Clausen explains.
Source: Krone
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