Blocked Membrane Translocators Initiate Cell Death Response

A team of molecular biologists has shown that certain antibiotics that kill bacteria by inhibiting protein transcription also cause the blockage and destruction of translocators, microtubules that transport macromolecules through organelle and cell membranes.

Investigators from Princeton University (NJ, USA) studied the Sec complex of translocators in Escherichia coli. They found that the antibiotics tetracycline and chloramphenicol, which inhibit ribosomal function, generated ribosome-polypeptide particles that became stuck in the translocators and plugged them up. In response, the cell activated the protease FtsH, which digested portions of the translocators and contributed to death of the cells. Increasing the amounts or the stability of the membrane protein YccA, a known inhibitor of FtsH, counteracted this destruction.

The findings from this bacterial system, which were published in the August 7, 2009, issue of the journal Science, may contribute to a better understanding of cancer therapeutics, since YccA is a functional homologue of the protooncogene product Bax inhibitor-1, which may share a similar mechanism of action in regulating apoptosis in mammalian cells.

"If we are to have any hope of outpacing the antibiotic resistance obtained by bacteria, it is paramount that we fully understand the mechanism of action of the antibiotics we currently use,” said first author Johna van Stelten, a graduate researcher in molecular biology at Princeton University. "Unfortunately, this is often very difficult as evidenced by the fact that, 50 years on, we are still learning new things about them. We have determined how YccA works in preventing stress-induced death in bacteria. We hope this new information will shed light on the mechanism of BI-1 in humans.”

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