Rockefeller University scientists have analysed soils from beaches, forests, and deserts on five continents and discovered the best places in the world to mine untapped antibiotic and anticancer drugs. The findings, published in the open-access journal eLife, provide new insights into the natural world as well as a road map for future drug discovery. The scientists now want to collect more samples from unique environments such as caves, hot springs, islands and city parks. They will continue with their citizen science effort, Drugs from Dirt, inviting the public to submit samples.
Samples were collected from a lake near the Seward mountains in Alaska. Image credit: Sean Brady
For this study, one hundred and eighty five samples were taken from rainforests, temperate forests, deserts, and beaches on five continents (North America, South America, Africa, Asia and Australia) and the oceanic islands of Hawaii and Dominican Republic. The study of the “biosynthetic” content of these soils shows their potential for drug discovery.
“Uncultured bacteria from the environment could provide a dazzling array of new molecules, many of which could become new medicines,” says lead author and postdoctoral fellow Zachary Charlop-Powers from The Rockefeller University in New York.
“The unbelievable diversity we found is a first step towards our dream of building a world map of chemicals produced by microbes -- similar to Google Earth’s and others’ maps of the world’s geography,” says Dr Sean Brady, head of the Laboratory of Genetically Encoded Small Molecules also at The Rockefeller University in New York.
The vast majority of antibiotics in clinical use today are derived from soil bacteria, but the yield of new drugs is low because the same cultivated bacteria, and the set of molecules they synthesise, are repeatedly rediscovered. However, for every cultured bacterial species, there are 100 uncultivated species in the environment.
Scientists have previously identified clusters of bacterial genes that are particularly good at producing therapeutics. This knowledge meant the scientists could focus on searching for certain types of gene clusters in samples rather than having to sequence and analyse the whole genomes of bacteria.
The team compared environmentally derived DNA to DNA from laboratory-grown bacteria chosen for their ability to make more than 400 natural product compounds. The analysis revealed soils particularly rich in important gene clusters.
For example, in a hot spring sample from New Mexico, they found clusters similar to those that produce epoxamicin. Epoxamicin is a natural molecule used as the starting point for a number of recently approved anticancer agents. In samples from Brazil, they found genes that may be able to make new versions of bleomycin, an anticancer agent listed on the World Health Organisation’s list of essential medicines.
Throughout the American southwest, they identified soil samples predicted to contain bacteria that make rifamycin-like antibiotics. Rifamycin is a key antibiotic used in the treatment of tuberculosis, although resistance has compromised its utility.
“We predict that soils from the American southwest should be useful for identifying new rifamycin derivatives with potential as nature’s solution to resistant TB,” says Dr Brady.
The scientists were also able to identify hotspots for ‘biosynthetic dark matter’ – gene clusters new to science. These clusters might produce molecules with novel structures and therefore unexplored functions.
“Based on the historical success of natural products as therapeutics, biosynthetic dark matter is likely to hold enormous potential for biomedicine,” says Dr Brady.
“We hope that efforts to map nature’s microbial and chemical diversity will result in the discovery of both completely new medicines and better versions of existing medicines,” he says.
We spoke to Dr Sean Brady, head of the Laboratory of Genetically Encoded Small Molecules at The Rockefeller University, about his work.
1. If the natural environment is such a rich source of potentially valuable new drugs, what are the implications for the protection of wildernesses?
SB: Once lost, it is very difficult to regain the genetic diversity of the world. I hope these types of studies demonstrate that there is a real, tangible benefit to human health of conserving diversity including the chemicals organisms can create. I should also say that while we are sequencing DNA from around the world we do not plan to clone any gene clusters from other countries. We believe that each nation should control the use of its own biodiversity. We hope the data we generate will allow others to make informed decisions about how best to benefit from the tremendous biosynthetic diversity hidden in the environment.
2. In previous work, you found that arid soils harbour the richest diversity of natural products from microbes, whereas brackish sediments and pine forest soils yield the least. Did the current study confirm this?
SB: Yes, that finding still stands: the arid soils of the American southwest are still among some of our most biosynthetically diverse soils along with a number of the Brazilian samples. In this study we didn’t look at enough additional brackish samples to really say whether the same is true other regions.
3. How much of a global contribution did the citizen science project make?
SB: We received samples via citizens from several different countries. However, most soils from the public were domestic. This is just the start of our citizen science effort but it bodes well for the future. We really hope to get high school students from around the world interested in the project. I think this is a great way to excite and teach students about both chemistry and biology.
4. What most surprised you about your findings?
SB: The unbelievable diversity we see as we sequence DNA from different environments is really interesting to us. Almost every sample we sequence is different from the last one we looked at.
5. What is the combined impact of your discoveries with a recent paper from the Northeastern University, Boston? E.g. could some of the bacteria you have mapped be brought into the lab with the new techniques?
SB: Dr. Lewis from Northeastern University has developed a method to culture previously uncultured organisms (iCHiP). In my laboratory, we have been pioneering methods to use DNA extracted directly from the environment - bypassing the need to culture the organisms at all. I think there is room for both approaches and I hope there will be increasing interest in this field as more bioactive compounds are discovered in the soil around us.
6. Teixobactin has been welcomed as the first new class of antibiotics for 25 years. What is the potential for making similar discoveries from the natural environment?
SB: This illustrates the power of the approach we are advocating. Lets say a new antibiotic like teixobactin is found and we are interested in finding more molecules like it – wouldn’t it be great if you could go to a database and identify an environment or a particular location that has genes capable of making additional Teixobactin-like molecules? As it turns out, teixobactin belongs to one of the classes of biosynthetic genes we investigated in this study and we are currently looking to see if we can identify teixobactin-like sequences in our datasets. If we find a sequence in the datasets, then we could potentially produce another teixobactin by cloning the teixobactin-like gene cluster from these these samples and characterizing the compound it encodes. It’s a methodology we’ve been developing in my lab for a number of years and we are routinely doing it. There is a lot of promise for discovering both new small molecules and derivatives of known molecules using these methods. Having this repertoire will increase the range of possible functions, for example reducing side effects or improving antibiotic resistance.
7. In your paper you say that the most diverse samples mapped to Atlantic forest and desert environments. What are the implications of this? Were they rich in genes that code for particular types of potential therapeutics?
SB: This data suggests these sites have a high diversity of genes with a history of making biomedically interesting small molecules. We think they would be good starting points for future discovery efforts focused on identifying both novel therapeutics and new versions of existing therapeutics.
8. How long might it be before a more comprehensive global natural product Atlas is available for drug discovery?
SB: While sequencing each individual sample is quite cheap, sequencing on a global scale will require significant financial resources. As the cost of sequencing gets cheaper, I think we will see many more data points added to our current set of locations. The cost of sequencing has already dropped by ten times since we began this project so it will get easier to sequence a greater number of samples. In the near term, we would love to look at a minimum of one sample from every state in the United States and one from every country around the world. We are also focusing on collecting samples from unique environments we haven’t yet explored. For example, caves, islands, city parks, additional hot springs etc.
Media contacts
Emily Packer
eLife
e.packer@elifesciences.org
+441223855373
