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Bacterial Battle Generates New Antibiotics

Scientists have revealed the hidden diversity of natural antibiotics using a new approach that pits one type of bacteria against another.
March 17, 2008

Scientists at MIT encouraged bacteria to produce a novel antibiotic by pitting them against a microbial enemy. The newly discovered compound can kill H. pylori, bacteria linked to stomach ulcers. The approach could provide a new way to discover novel antibiotics and shed light on how and when bacteria churn out these toxic compounds.

Bacterial battle: Scientists have discovered a new antibiotic, isolated from the bacterium Rhodococcus fascians. When dripped onto a paper disc (white) in the middle of a plate full of other bacteria (orange), the new antibiotic kills the bacteria.

“The lab is a tame place if you’re a bacterium: you don’t have to fight for a crystal of sugar,” says Philip Lessard, a molecular biologist at MIT who collaborated on the work. “So maybe we’re not seeing them spitting out chemical-warfare compounds like they would normally.”

Antibacterial resistance–when bacteria become invincible to a particular drug–is becoming a major crisis in American hospitals. According to the Centers for Disease Control and Prevention, approximately two million Americans acquire infections while in hospitals every year, 90,000 of which are fatal. About 70 percent of those infections are resistant to at least one type of antibiotic.

Scientists across the globe are looking for ways to make new antibiotics. Some projects involve melding existing drugs into potent new molecules, while other approaches focus on designing new drugs that target specific mechanisms of microbial resistance. But recent sequencing studies suggest that bacteria possess an untapped well of novel antibiotics that they don’t produce under normal lab conditions, thereby remaining hidden to scientists for decades.

Scientists working in Anthony Sinskey’s lab at MIT sequenced the genome of a strain of soil-dwelling bacteria known as Rhodococcus fascians. They were surprised to find that this organism, not known for its antibiotic-producing powers, harbored a number of genes involved in the metabolism of antibiotic-like compounds. (In the wild, bacteria produce antibiotics as a survival mechanism, to clear themselves a niche in the crowded microbial world.)

While Rhodococcus seemed genetically capable of producing the compounds, the organisms did not do so in the lab–until, that is, they were grown alongside another type of bacteria, called Streptomyces, which are among the most prolific antibiotic producers in the microbial world. Microbiologist Kazuhiko Kurosawa and his colleagues published their discovery last month in the Journal of the American Chemical Society.

The novel compound, dubbed rhodostreptomycin, belongs to a class of antibiotics known as aminoglycosides, which include neomycin, used in many first-aid creams, and streptomycin, a tuberculosis drug. While it’s unclear if the drug would be appropriate for clinical use, early tests show that it can kill H. pylori, bacteria linked to stomach ulcers, and it can survive highly acidic environments like that of the stomach. The molecule also appears to contain a novel structural component, which could provide a jumping-off point for chemists keen to design new drugs. “This opens a new domain in the chemical-diversity space,” says Lessard.

Scientists don’t yet know exactly how the Rhodococcus strain acquired the ability to make this new toxin. Only one out of a number of flasks of Rhodococcus growing with enemy Streptomyces produced the antibiotic. Kurosawa and his colleagues discovered that the drug-producing strain contains a large chunk of DNA from the other organism. While previous research suggests that DNA swapping between bacteria is quite common–it’s thought to underlie bacteria’s ability to quickly evolve drug resistance–the exchange has been difficult to observe firsthand. “In this case, the process is caught in the act, and you can see the consequences,” says Jon Clardy, a chemist at Harvard Medical School, in Boston.

The work has elicited excitement from scientists developing novel antibiotics because the method could provide a new way to uncover the hidden antibiotic-producing abilities of different kinds of bacterium. “Advances in sequencing technology are now making it possible to see how the diversity of known antibiotics has come from gene swapping,” says Michael Fischbach, a microbial geneticist at the Broad Institute, in Cambridge, MA. Fischbach is overseeing a project to sequence 16 strains of the Streptomyces, in which scientists will try similar methods to coax out new drugs.

Previous sequencing research suggests that some strains have the genetic ability to produce 20 to 30 different antibiotics, but when grown on their own in comfortable lab conditions, they produce only two or three. “Where are the other 90 percent?” asks Fischbach. “I think [Kurosawa’s] approach is the right way to explore this.”

It’s not yet clear if the swapped piece of DNA contains genes for the antibiotic itself or if it triggers a regulatory mechanism that warns Rhodococcus of encroaching bacteria, turning on an inherent but often silent mechanismto make toxins. So far, the researchers have sequenced only half of the DNA insert; they expect to sequence the other half soon.

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