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Speaker on New Drug Discovery Methods

By Toby Aicher

Rockefeller University Professor of Chemical Biology Sean Brady gave a talk last Friday, March 18 titled “Watch Your Step: There’s New Chemistry Everywhere.” Brady uses a genetic sequencing approach to search for new antimicrobial compounds in previously uncharacterized bacteria in soil samples. He described his research with two phrases: “new drugs from new bugs” and “drugs from dirt.”

We derive many of our therapeutic drugs from nature. For instance, Alexander Flemings first isolated penicillin in 1928 from a mold that accidently killed the bacteria he was researching in a lab. Microbes fight in evolutionary arms races with other microbes, and have evolved biosynthetic pathways that produce antimicrobial compounds to protect themselves. We can exploit their natural arsenals for our own medical benefit.

“One thing we can clearly find is that nature is playing with resistance,” Brady said. “We can find molecules in nature that have better activity against bacteria. The resistance we fight in the clinic is no different than the resistance that bacteria are fighting out in the environment.”

The search for new antibiotics has assumed a new urgency as bacteria have begun to evolve resistance to our antibiotics. The World Health Organization recently issued a report on antibiotic resistant bacteria, saying, “it is a problem so serious that it threatens the achievements of modern medicine. A post-antibiotic era, in which common infections and minor injuries can kill, far from being an apocalyptic fantasy, is instead a very real possibility for the 21st century.”

Traditionally, drug hunters have isolated bacteria from the environment and grown them up in a lab in order to characterize the chemicals they produce. This approach yielded dozens of useful antibiotics in the 20th century. But Brady argued that traditional approaches are inadequate and inefficient and that new methods are needed to find antibiotic resistant drugs.

One problem with the traditional method of growing environmental bacteria in the lab is that the vast majority of microbes present in environmental samples don’t grow. Even microbes that do grow in the lab don’t express all their enzymes, so we don’t know the full repertoire of compounds they produce.

“As successful as the traditional approach has been, there are some weird quarks about it,” Brady said. “If you think about it, the approach is almost 100 years old, and there aren’t too many fields of science that you could argue you are doing the exact same thing as 100 years ago. Over the past decade there has been a recognition of the key limitations of the approach.”

To remedy these problems, Brady has developed a new method for discovering natural products using genetic sequencing. First, he collects soil from an environment. So far his lab has gathered thousands of soil samples from across the world, from the Amazonian rainforest to the Sahara dessert. Next, he isolates DNA from the all bacteria in the soil. Unlike culturing bacteria, which favors the growth of a few species, DNA collection insures that almost all the bacteria in a sample are represented. Then he creates a library of all the biosynthetic gene clusters, which are packets of genes that create natural products. Most biosynthetic gene clusters have conserved sequence regions, which act as molecular tags or barcodes, that allow his lab to sift through the library of biosynthetic gene clusters and search for new biosynthetic gene clusters that are related to already known biosynthetic clusters that produce interesting and useful compounds. Finally, he takes a biosynthetic gene cluster of interest and artificially transfers it into bacteria in the laboratory to analyze the product it produces.

“We can take any drug structure we want to identify, and we can go back and systematically interrogate the world for it and ask if we can find better versions of that drug,” Brady said.

Brady’s method for drug discovery has already yielded promising results. One example he used was his lab’s efforts to find new, more effective versions of an antibiotic drug called Daptomyocin.

“Daptomyocin is considered the first antibiotic to have a new mode of actioin 20 years. It makes Merck a billion dollars. They tell us it’s really rare – no it’s not rare, we can go find lots of daptomyocin-like  structures out in nature, and we’re  beginning to investigate new daptomyocin from soil samples.”

In addition to finding biosynthetic gene clusters that make compounds similar to already known compounds, his lab has also identified novel biosynthetic gene clusters with unknown products.

“As we survey the world and generate millions of new sequences tags, about  five percent of our sequence tag trace back to something we know, but about 95 percent of our sequences are new. We are trying to find ways to use this information to guide the discovery of novel compounds.

Brady’s new method for drug discovery is changing how scientists search for medically relevant compounds in nature, and hopefully will yield new drugs that will enable doctors to fight antibiotic diseases in the future.

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