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Bacteria engage in chemical warfare against viruses

Bacteria have plenty of ways to combat the viruses that plague them, called phages. The CRISPR-Cas system and restriction enzymes that cleave phage DNA are the best understood, but there are others. They use a variety of different mechanisms and stop phages at various stages of infection, but they all rely on biological actors: proteins and RNA.

New work has just revealed, though, that bacteria can use chemical weapons as well.

Bacteria produce a wide range of active small molecules that are not essential for survival but do confer a growth advantage. Some of these small molecules, which kill their fellow microbes, are already used (by us) as antibiotics. It was also observed, more than fifty years ago, that bacteria make molecules that can inhibit the growth of phages. But it wasn't clear whether these molecules are made specifically because they slow down the phages. Only now, with the background knowledge that (a) bacteria make a lot of bioactive compounds, many of which do combat other microorganisms, and that (b) phages are a major scourge for bacteria, did researchers think to check.

Biochemists screened 4,960 compounds for their ability to protect E. coli from phage infection and found 11 that could. Nine out of the 11 were what are termed DNA-intercalating agents. The nucleotides that comprise DNA (A,T, C, and G) are flat molecules, and they're stacked parallel to each other along the DNA helix. DNA-intercalating agents slide in between them, interfering with the copying of DNA during cell division.

Streptomyces are soil bacteria that are a veritable storehouse of drugs. They make more than two-thirds of the antibiotics we use, and they make four of the DNA-intercalating compounds identified in this screen, which happen to already be in use as anticancer agents. To determine if these molecules function in the wild to deter phage infection like they do in the lab, the scientists collected Streptomyces from across the globe—Bangladesh, Canada, China, India, Jamaica—and subjected them to a battery of experiments.

They found that the DNA-intercalating agents (the chemicals daunorubicin and doxorubicin were the representatives used) made by these bugs were effective at protecting them from phage infection and that the ability to make them is fairly well conserved; about 30 percent of the Streptomyces strains they examined could do it.

The agents block a step early in the infection: after the phage injects its DNA into the bacterial host cell but before that DNA is copied. The authors speculate that the phage DNA is particularly vulnerable at this point to the low levels of intercalating agents made by the bacteria, perhaps because it has not yet accumulated a protective shield of DNA-binding proteins. These chemicals effectively block the replication of all double-stranded DNA phages. Since they can diffuse out of the cell that makes them, the cells that produce them might defend an entire bacterial community.

Biologists have long relied on intercalating agents to visualize DNA: ethidium bromide is visible under ultraviolet light and is used to stain DNA in the lab; propidium iodide is a red fluorescent dye commonly used to see the relative DNA content of cells during cell cycle analysis (it helps us distinguish between those cells that have copied their DNA but not yet divided from those that haven't). But bacteria, apparently, have used them for far longer than we have.

, 2018. DOI: 10.1038/s41586-018-0767x(About DOIs).