Harnessing Soil Microbes May Improve Cancer Drug Development

A team of scientists recently created a novel process to discover compounds from soil that could be used to create anticancer drugs.

This drug discovery process can efficiently discover new enediyne natural products from soil microbes, according to a study published by mBio. The study showed that microbial natural products can provide numerous drug candidates, especially anticancer agents.

“The enediynes represent one of the most fascinating families of natural products for their extraordinary biological activities,” said lead researcher Ben Shen, PhD. “By surveying 3400 strains from the TSRI collection, we were able to identify 81 strains that harbor genes encoding enediynes. With what we know, we can predict novel structural insights that can be exploited to radically accelerate enediyne-based drug discovery and development.”

The investigators first prioritized microbes from their strain collection to identify which are predisposed to create certain natural products. This process can save time, money, and other resources compared with the standard approach, according to the study.

Through this process, the researchers discovered a novel family of enediyne natural products called tiancimycins. These products are able to selectively kill cancer cells more rapidly and completely compared with toxic molecules in FDA-approved antibody-drug conjugates, which are monoclonal antibodies attached to drugs that target cancer cells, according to the study.

The investigators also discovered multiple novel natural producers of C-1027 that produces more of the antibiotic than the current method. C-1027 is currently in clinical development as an anticancer antibiotic.

It has been more than 10 years since Dr Shen reported C-1027 enediyne biosynthetic machinery. He hypothesized that the discovery of C-1027 and other enediynes could be used for the discovery of natural products.

“The work described by the Shen group is an excellent example of what can be achieved by coupling state of the art genomic analyses of potential biosynthetic clusters and modern physicochemical techniques,” said David J. Newman, retired chief of the National Cancer Institute’s Natural Products Branch. “As a result of their work, the potential number of enediynes has significantly increased.”

This method of strain prioritization and genome mining leads to a more proficient use of resources, including finances, that are involved with the discovery process. By only researching strains that create the most important natural compounds, the investigators avoided spending time on compounds that will not translate to new drugs, according to the study.

“This study shows that the potential to rapidly discover new enediyne natural products from a large strain collection is within our reach,” said co-first author Xiaohui Yan, PhD. “We also show the feasibility of manipulating tiancimycin biosynthesis in vivo, which means that sufficient quantities of these precious natural products can be reliably produced by microbial fermentation for drug development and eventual commercialization.”