An analysis of bacterial communities in soil samples from around the world reveals unexplored diversity in biosynthetic enzymes

Moore, Bradley S

Zhang, Jia Jia

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PubMed

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UC San DiegoUC San Diego Previously Published WorksTitleDigging for biosynthetic dark matterPermalinkhttps://escholarship.org/uc/item/61b667q2JournaleLife, 4(February2015)ISSN2050-084XAuthorsZhang, Jia JiaMoore, Bradley SPublication Date2015DOI10.7554/elife.06453 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of Californiaelifesciences.orgINSIGHTNATURAL PRODUCTSDigging for biosyntheticdark matterAn analysis of bacterial communities in soil samples from around theworld reveals unexplored diversity in biosynthetic enzymes.JIA JIA ZHANG AND BRADLEY S MOORERelated research article Charlop-Powers Z,Owen JG, Reddy BV, Ternei MA,Guimaraes DO, de Frias UA, Pupo MT,Seepe P, Feng Z, Brady SF. 2015. Globalbiogeographic sampling of bacterialsecondary metabolism. eLife 4:e05048.doi: 10.7554/eLife.05048Image Soil samples were collected fromfive continents as part of a citizen-scienceproject called ‘Drugs from Dirt’Researchers have long been interested innatural products—small molecules pro-duced by an organism that are not directlyinvolved in its normal growth, developmentor reproduction—as potential new medicines.However, despite success in the past, mostpharmaceutical companies have abandoned nat-ural product drug discovery efforts over the lastdecade because it has been difficult to reliablyaccess a sufficient supply of these compounds.Moreover, efforts to find new bioactive chemicalshave frequently ‘re-discovered’ the same chem-ical compounds (Li and Vederas, 2009).Recently, research in the field has been revi-talized by the realization that most natural productsare encoded by clustered sets of genes that canbe identified from genome sequence data ofbacteria or bacterial communities. New findingssuggest the biosynthetic potential of microbesactually remains largely untapped, as many‘talented producers’ of small molecules cannotcurrently be cultured in the lab (Wilson et al., 2014).Furthermore, even bacteria that do grow in thelab possess more biosynthetic gene clusters thanthe number of natural products experimentallyisolated from them (Cimermancic et al., 2014).For the first time, modern high-throughputsequencing technologies provide a means forsensing previously undetected ‘biosyntheticdark matter’.Now, in eLife, Sean Brady of RockefellerUniversity and colleagues from the US, Brazil,South Africa and China—including ZacharyCharlop-Powers as first author—leverage thisknowledge to explore biosynthetic diversityfrom across the globe (Figure 1). As part ofa citizen science project called ‘Drugs from Dirt’,the public was invited to collect and submit soilsamples from around the world. Combiningthese with other soil samples gave a total of96 samples from five continents and severaloceanic islands. Charlop-Powers et al. thenamplified, by PCR, conserved regions of genesfor two enzymes involved in producing manynatural products (namely non-ribosomal peptidesynthetase and polyketide synthase). Next,they undertook a large-scale sequencing effortto identify and compare these two biosyntheticgenes from this sampling of soil-dwelling bacteria(Charlop-Powers et al., 2015).The researchers found that the geographicallocation was the single most important factorthat determined the sequence composition ofthe two biosynthetic genes. By systematicallycomparing sequence compositions to identifythose that were most similar in the samplesstudied, Charlop-Powers et al. found that thestrongest sequence overlap belonged to samplescollected in close physical proximity to oneCopyright Zhang and Moore. Thisarticle is distributed under the terms ofthe Creative Commons AttributionLicense, which permits unrestricted useand redistribution provided that theoriginal author and source are credited.Zhang and Moore. eLife 2015;4:e06453. DOI: 10.7554/eLife.06453 1 of 3another. Very little overlap was observed be-tween samples collected from different globallocations (less than 3%), even if they werecollected from similar biomes (that is, regionswith similar climates and ecosystems).At the same time, biosynthetic sequence com-position was influenced by biome-type on a morelocal level. When the researchers compared sevensamples collected in New Mexico—one from a hotspring and six from arid topsoil biomes—theyfound that sequences from the dry soil sampleswere more similar to each other than to the samplecollected from the hot spring, even though somedry sampling sites were physically closer to the hotspring than to each other. Additionally, samplescollected from different sites spanning three Brazil-ian biomes (aquatic, forest, and tropical savanna)were most strongly related to samples collectedfrom the same Brazilian biome and only distantlyrelated to samples from other biomes, regardlessof how close they were geographically.Upon reflection, the findings from this smallsampling of biosynthetic diversity are not sosurprising. Previous studies have demonstratedconvincing evidence that biosynthetic genes andgene clusters are frequently exchanged by hori-zontal gene transfer (Ziemert et al., 2014), andmicrobes can only share genetic material in thismanner if they can physically interact. The factthat biome-type also has an influence on sequencecomposition indicates that natural products mayplay significant roles in microbial ecology.What are those roles? For the most part, wehave no idea. The ability to make natural pro-ducts is clearly important, as many well-studiedsoil bacteria devote significant portions of theirgenomes to the production of natural products,in some cases up to 10% (Udwary et al., 2007).It has long been assumed that these compoundsare defensive, as many natural products haveantibiotic activity and confer fitness benefits toproducers competing for nutrients (Kinkel et al.,2014). However, doses of these compounds thatare too low to inhibit or kill other microbes canstill alter their gene expression, and this scenariomay be more relevant in the environment(Goh et al., 2002). Given the vast diversity ofbiosynthetic potential uncovered in this survey,are the functions and impacts of natural productsin the environment equally varied?Although the work of Brady, Charlop-Powersand co-workers cannot offer direct answers tothese questions, it does offer a more tangiblecontribution to drug discovery efforts. By usingknown sequences from characterized geneclusters, the researchers identified samplesenriched with biosynthetic genes similar tothose associated with biomedically relevantcompounds. These biosynthetic ‘hot spots’may serve as starting points to search forstructurally similar molecules with, hopefully,equally potent activities. The challenge now willbe to work out how to translate sequenceinformation into chemical reality, and further,how to begin to access not just small variationsin old chemistry, but completely new chemicalscaffolds.Jia Jia Zhang is in the Center for Marine Biotechnologyand Biomedicine, Scripps Institution of Oceanography,University of California, San Diego, San Diego, UnitedStatesBradley S Moore is in the Skaggs School of Pharmacyand Pharmaceutical Sciences and the Scripps Institutionof Oceanography, University of California, San Diego,San Diego, United Statesbsmoore@ucsd.eduCompeting interests: The authors declare that nocompeting interests exist.Published 13 February 2015ReferencesCharlop-Powers Z, Owen J, Reddy B, Ternei M,Guimaraes D, de Frias U, Pupo M, Seepe P, Feng Z,Brady S. 2015. Global biogeographic sampling ofbacterial secondary metabolism. eLife 4:e05048.doi: 10.7554/eLife.05048.Cimermancic P, Medema MH, Claesen J,Kurita K, Wieland Brown LC, Mavrommatis K,Pati A, Godfrey PA, Koehrsen M, Clardy J, et al.2014. Insights into secondary metabolism froma global analysis of prokaryotic biosyntheticgene clusters. Cell 158:412–421. doi: 10.1016/j.cell.2014.06.034.Figure 1. Unearthing biosynthetic diversity in soil-dwelling bacteria. Charlop-Powers et al. undertooka large-scale PCR and sequencing effort to identify andcompare biosynthetic genes from bacterial communitiesin soil samples collected from around the world.FIGURE CREDIT: PHOTOGRAPH BY ABRAHIM EL GAMAL.Zhang and Moore. eLife 2015;4:e06453. DOI: 10.7554/eLife.06453 2 of 3Insight Natural products | Digging for biosynthetic dark matterGoh EB, Yim G, Tsui W, McClure J, Surette MG,Davies J. 2002. Transcriptional modulation ofbacterial gene expression by subinhibitoryconcentrations of antibiotics. Proceedings of theNational Academy of Sciences of USA 99:17025–17030. doi: 10.1073/pnas.252607699.Kinkel LL, Schlatter DC, Xiao K, Baines AD. 2014.Sympatric inhibition and niche differentiation suggestalternative coevolutionary trajectories amongStreptomycetes. ISME Journal 8:249–256. doi: 10.1038/ismej.2013.175.Li JW, Vederas JC. 2009. Drug discovery and naturalproducts: end of an era or an endless frontier? Science325:161–165. doi: 10.1126/science.1168243.Udwary DW, Zeigler L, Asolkar RN, Singan V, LapidusA, Fenical W, Jensen PR, Moore BS. 2007. Genomesequencing reveals complex secondary metabolome inthe marine actinomycete Salinispora tropica.Proceedings of the National Academy of Sciences ofUSA 104:10376–10381. doi: 10.1073/pnas.0700962104.WilsonMC, Mori T, Rückert C, Uria AR, Helf MJ, TakadaK, Gernert C, Steffens UA, Heycke N, Schmitt S, et al.2014. An environmental bacterial taxon with a large anddistinct metabolic repertoire. Nature 506:58–62.doi: 10.1038/nature12959.Ziemert N, Lechner A, Wietz M, Millán-Aguiñaga N,Chavarria KL, Jensen PR. 2014. Diversity andevolution of secondary metabolism in the marineactinomycete genus Salinispora. Proceedings ofthe National Academy of Sciences of USA 111:E1130–E1139. doi: 10.1073/pnas.1324161111.Zhang and Moore. eLife 2015;4:e06453. DOI: 10.7554/eLife.06453 3 of 3Insight Natural products | Digging for biosynthetic dark matter

Digging for biosynthetic dark matter

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Digging for biosynthetic dark matter.

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