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Biological Chemistry

Direct Route To Natural Products

Drug Discovery: Technique zeroes in on microbes that biosynthesize specific compound families

by Stu Borman
October 3, 2014 | A version of this story appeared in Volume 92, Issue 40

Graphic shows a real-time PCR technique that saves time and effort in natural product drug discovery by screening microbes for those that biosynthesize desired compound families.
Credit: J. Nat. Prod.
A real-time PCR technique saves time and energy in natural product drug discovery by screening microbes for those that biosynthesize desired compound families.

Natural products from plants and microbes are one of the most prolific sources of drug leads and approved medications. But traditional natural product drug discovery programs are expensive and time-consuming.

A new approach might streamline the discovery process by pinpointing microbial strains capable of biosynthesizing compounds in specific natural product families. The technique was developed by Yanwen Duan of Central South University, in Changsha, China; Ben Shen of Scripps Research Institute Florida; and coworkers (J. Nat. Prod. 2014, DOI: 10.1021/np5006168).

In many cases, researchers have already identified the genes that encode the biosynthetic pathways for making particular classes of natural products. In the new method, Duan, Shen, and coworkers use an existing technique, called real-time polymerase chain reaction (PCR), to single out microbes that express such genes.

The researchers demonstrated the method by using it to evaluate a collection of about 1,900 actinomycete bacterial strains to identify those that biosynthesize diterpenoids, such as the antibiotics platensimycin and platencin. Their real-time PCR evaluation found about one-fourth of the library was capable of producing diterpenoids. Of the resulting 488 microbes, six turned out to be previously unidentified platensimycin and platencin producers.

Scientists at Merck Research Laboratories discovered platensimycin and platencin in 2006, when they painstakingly screened a collection of 83,000 microbes for promising natural products (Nature 2006, DOI: 10.1038/nature04784). In that study, the researchers analyzed many more bacteria than did Duan, Shen, and coworkers, but they didn’t know in advance what class of compounds they were searching for.

Duan, Shen, and coworkers say the technique has the potential to find new bioactive compounds in diterpenoid and other natural product families. However, they have yet to search for these. The team filed a provisional U.S. patent application for the method.

David J. Newman, chief of the National Cancer Institute’s Natural Products Branch, points out that the new method will complement rapid techniques, developed by several groups in the past few years, for finding bioactive natural products of unknown structure. “The new method works beautifully if, to some extent, you know what base molecule you’re looking for,” he says. “From that point of view, it’s probably by far the simplest way of finding something.”



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