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%20(2).jpg "Growth of bacteria when only antitoxin is induced (left), only toxin is induced (middle), and both are induced together (right)")
Bacteria can be veritable poison factories. In addition to those that harm humans, such as tetanus and botulism, or the toxins they produce to compete with other microorganisms, we now know that bacteria can produce poisons especially for committing suicide. Indeed, many bacteria carry around a sort of “suicide pill,” which comes with its own antidote. To do itself in, the bacterium simply does away with the antidote. Recent Weizmann Institute research revealed many novel versions of these suicide pills in bacteria and showed that they help the bacteria resist viral attacks.
Suicide is most often a last-ditch response to one of the viruses that invade bacterial cells. If the cell cannot overcome the infection, it may take its own life to prevent the virus from spreading to neighboring bacteria. Understanding how the suicide pill mechanism works may, on the one hand, help protect useful bacteria like those in yogurt cultures from viral assault and, on the other, lead to the development of new antibiotic drugs against harmful bacteria. In addition, it could yield new insights into treating such scourges as tuberculosis.
Dr. Rotem Sorek and his team in the Institute’s Molecular Genetics Department, working with Dr. Udi Qimron of Tel Aviv University, discovered the suicide mechanism using a method for identifying toxic bacterial genes that he had developed several years ago, when he realized that a drawback of a common technique for sequencing bacterial genomes could be a unique research tool in disguise. The technique of genome sequencing involves cutting up the bacterial genome and inserting the pieces into another bacterium – E. coli – for duplication and further sequencing. But this method always left gaps in the sequence. Sorek understood that the missing genes encoded toxins that killed the host E. coli cells. Building on this insight, he developed a computerized method for identifying these killer genes. Recently, together with his research team, he created an online database called PanDaTox containing some 40,000 sequences for genes encoding bacterial toxins.
But some instances of cell-killing genes seemed to be less than clear-cut: While many of the toxins killed the host E.coli cells outright, others seemed to be more sporadic – destroying them only part of the time. This led Sorek and his team to surmise that certain suicide mechanisms involve pairs of genes – one for a toxin, the other for an antitoxin.
In their study, which appeared recently in Molecular Cell, Sorek and research students Hila Sberro and Dr. Azita Leavitt went looking for toxin-antitoxin pairs. Their quest involved analyzing the results after inserting over a million genes from hundreds of microbial genomes into E. coli cells. When only the toxin gene was present, the E. coli cells died, but when both toxin and antitoxin were present, the genes for both were cloned in the cells. The researchers tentatively sorted into different families all of the toxin-antitoxin pairs they identified and explained how they function.
The team found that the toxin-antitoxin mechanism works something like a booby trap. The toxin molecule – which, as they discovered, can come in many different forms – is highly stable. The antitoxin that fits it, however, is a sort of hair-trigger component that is fragile and easily destroyed, so the supply must be constantly renewed. So when a virus takes over the cell and attempts to hijack its DNA production machinery, the frail antitoxin is destroyed, leaving the toxin free to kill the cell and the viruses along with it.
Among other things, the study may yield some important insights into such hard-to-treat diseases as tuberculosis. Not only are new strains of TB appearing that are increasingly resistant to known antibiotics, but even the common forms of the disease require many months of treatment to rid the body of all the pathogens. The research helps explain why. TB-causing bacteria contain unusually large numbers of toxic genes, and the team identified some new ones. Their findings support the idea that some of those toxin-antitoxin mechanisms merely cause the cells to fake their own suicides: Though they appear to be dead, these cells are actually only dormant. Since only active cells are killed by the antibiotic drugs, these must be administered until all the bacteria have come out of dormancy. In the future, says Sorek, methods to prevent dormancy could shorten and improve TB treatment.
The findings have also yielded a number of new insights into the strategies that bacteria use in their evolutionary battle with viruses, and these, in turn, may have implications for industry as well as biomedical research. For instance, food industries that rely on bacterial cultures have already shown interest in new methods for boosting bacterial resistance to viral infection. The same findings might, in the future, lead to the development of novel antibiotic drugs based either on the new types of toxin molecules the team discovered or on substances that can interfere with the toxin-antitoxin mechanism.
Dr. Rotem Sorek’s research is supported by the Y. Leon Benoziyo Institute for Molecular Medicine; the Abisch Frenkel Foundation for the Promotion of Life Sciences; the European Research Council; the Leona M. and Harry B. Helmsley Charitable Trust; and the Hugo and Valerie Ramniceanu Foundation. Dr. Sorek is the incumbent of the Rowland and Sylvia Schaefer Career Development Chair in Perpetuity.
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