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The Antimicrobial Potential of Streptomyces from Insect Microbiomes

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The Antimicrobial Potential of Streptomyces from Insect Microbiomes ARTICLE https://doi.org/10.1038/s41467-019-08438-0 OPEN The antimicrobial potential of Streptomyces from insect microbiomes Marc G. Chevrette 1,2, Caitlin M. Carlson2, Humberto E. Ortega3, Chris Thomas4, Gene E. Ananiev5, Kenneth J. Barns4, Adam J. Book2, Julian Cagnazzo2, Camila Carlos2, Will Flanigan2, Kirk J. Grubbs2, Heidi A. Horn2, F. Michael Hoffmann5, Jonathan L. Klassen6, Jennifer J. Knack 7, Gina R. Lewin8, Bradon R. McDonald 2, Laura Muller2, Weilan G.P. Melo 3, Adrián A. Pinto-Tomás9, Amber Schmitz2, Evelyn Wendt-Pienkowski2, Scott Wildman4, Miao Zhao10, Fan Zhang4, Tim S. Bugni4, David R. Andes10, Monica T. Pupo 3 & Cameron R. Currie2 1234567890():,; Antimicrobial resistance is a global health crisis and few novel antimicrobials have been discovered in recent decades. Natural products, particularly from Streptomyces, are the source of most antimicrobials, yet discovery campaigns focusing on Streptomyces from the soil largely rediscover known compounds. Investigation of understudied and symbiotic sources has seen some success, yet no studies have systematically explored microbiomes for anti- microbials. Here we assess the distinct evolutionary lineages of Streptomyces from insect microbiomes as a source of new antimicrobials through large-scale isolations, bioactivity assays, genomics, metabolomics, and in vivo infection models. Insect-associated Streptomyces inhibit antimicrobial-resistant pathogens more than soil Streptomyces. Genomics and meta- bolomics reveal their diverse biosynthetic capabilities. Further, we describe cyphomycin, a new molecule active against multidrug resistant fungal pathogens. The evolutionary trajectories of Streptomyces from the insect microbiome influence their biosynthetic potential and ability to inhibit resistant pathogens, supporting the promise of this source in augmenting future antimicrobial discovery. 1 Laboratory of Genetics, University of Wisconsin-Madison, Madison 53706 WI, USA. 2 Department of Bacteriology, University of Wisconsin-Madison, Madison 53706 WI, USA. 3 School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-903 SP, Brazil. 4 Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison 53705 WI, USA. 5 McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, University of Wisconsin-Madison, Madison 53705 WI, USA. 6 Department of Molecular and Cell Biology, University of Connecticut, Storrs 06269 CT, USA. 7 Department of Biology, Large Lakes Observatory, University of Minnesota-Duluth, Duluth 55812 MN, USA. 8 School of Biological Sciences, Georgia Institute of Technology, Atlanta 30332 GA, USA. 9 Center for Research in Microscopic Structures and Department of Biochemistry, School of Medicine, University of Costa Rica, San José 10102, Costa Rica. 10 Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison 53705 WI, USA. Correspondence and requests for materials should be addressed to C.R.C. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:516 | https://doi.org/10.1038/s41467-019-08438-0 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-08438-0 he rapid emergence of antimicrobial resistance in bacterial eukaryotic hosts, ranging from sea squirts17 to humans18.A Tand fungal pathogens is a public health crisis1,2. Novel particularly compelling source of novel antimicrobials lies in therapeutics are needed to counter resistance, yet no new defensive symbioses, where bacterial symbionts produce anti- antimicrobial classes have been clinically approved in over three microbials to protect against opportunistic and specialized decades3. Natural products are the main source of antimicrobials, pathogens19–23. In insects, these symbioses are best exemplified in the majority of which are produced by Actinobacteria cultured fungus-growing ant19–21, solitary digger wasp22, and southern from the soil3,4. However, contemporary studies of this once pine beetle23 (Fig. 1a, right) systems, where Actinobacteria prolific source of novel chemistry face dramatically diminishing (typically Streptomyces) provide chemical defenses, paralleling returns, largely due to the rediscovery of known compounds5. our own reliance on the antimicrobials produced by these taxa to Efforts to address this issue, including genome mining6,7, syn- combat infectious disease. For example, the Streptomyces sym- thetic biology8, and exploring alternative microbial sources, such biotically associated with the southern pine beetle (Dendroctonus as marine microbial environments9–12 and underrepresented frontalis) produce the secondary metabolites frontalamide A, taxa13,14, have yielded limited success. To combat the continual frontalamide B, and mycangimycin23,24. Mycangimycin inhibits emergence of multidrug-resistant pathogens, there is a critical the beetles’ antagonistic fungus Ophiostoma minus and has potent and constant need to discover new antimicrobial natural inhibitory activity against malaria while the frontalamides have products. general antifungal activity23,24. Solitary wasps also associate with Natural products are the language of microbial interactions, Streptomyces that provide antibacterial and antifungal chemical evolved to mediate communication and antagonism among protection to their larvae through production of streptochlorin, a and between species15,16. Within microbiomes, the ecology and variety of piericidin analogs, and other molecules25. The anti- diversity of natural product chemistry reflect the underlying fungal compound sceliphrolactam was discovered from Strepto- interactions between the microbial community, host, and myces associated with a mud dauber wasp25. The natalamycin environment. Exploration of the specialized natural product derivatives produced by Streptomyces from the fungus-growing chemistry embedded within host microbiomes is an emerging termite system provide similar antifungal defense26. Further, over new paradigm in antimicrobial drug discovery. Antimicrobials 10 new natural products with antimicrobial activity have been have recently been discovered from the microbiomes of diverse identified from the chemical characterization of approximately Pine Symbiont Beetle Streptomyces Moths & Butterflies Ants, Bees, & Wasps HO O O O Beetles Flies 1 Other Host 1 insects Other Hawaii Tropical Beetle Pathogen Sub- tropical Biome Arctic Other Temperate Fungus-growing ant O 2 5 OH HO O O 50 O HO OH OH OHO O OH OH O OOH O O O 200 HO 2 O OH OH OH OH Fig. 1 Sampling strategy for Streptomyces from insect microbiomes. Streptomyces were isolated from a wide range of insects and geographies (1445 insects; 10,178 strains; dot size, insects sampled). Streptomyces production of the antifungal mycangimycin (1) in the Southern Pine Beetle system is shown at right. Cyphomycin (2) is a new antifungal described herein. Photo credits: southern pine beetle - Erich G. Vallery; fungus-growing ant – Alexander Wild 2 NATURE COMMUNICATIONS | (2019) 10:516 | https://doi.org/10.1038/s41467-019-08438-0 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-08438-0 ARTICLE 23,24,27,28 100 insect-Streptomyces strains . Globally there are over a 16S b S. xinghaiensis NRRL B-24674 SID5475 Core genome S. sp. M56 SID8382 fi S. sp. M27 SID8361 ve million insect species that occupy virtually every terrestrial S. rimosus ATCC 10970 SID5471 B01 S. sp. MspMP-M5 SID8354 S. celluloflavus NRRL B-2493 SID7805 29 S. sp. ISID311 niche . Although insects are among the most diverse organisms B02 S. sp. ScaeMP-e96 SID4951 29 S. sp. FxanaC1 SID8375 on the planet , studies of Actinobacteria from these systems have B03 S. sp. LamerLS-31b SID4921 n =36 c S. flavogriseus ATCC 33331 SID7815 fi B04 S. sp. SID7834 been limited to only a few insect orders, speci cally Hymenoptera n =38 S. sp. PalvLS-984 SID4941 S. sp. OspMP-M45 SID4925 B05 S. sp. DpondAA-B6 SID4912 S. sp. ScaeMP-e122 SID8358 and Coleoptera. Further, insects themselves exhibit complex n = 122 S. sp. SID3915 S01 S. sp. DpondAA-F4a SID4940 n =10 S. sp. DpondAA-F4a SID4939 chemistry that mediates and maintains the diversity of their S02 S. sp. DpondAA-A50 SID8360 C-I n =33 S. sp. DvalAA-83 SID8357 ecological interactions30. S03 S. sp. SirexAA-E SID1 n =5 S. sp. ScaeMP-e83 SID4937 d S. sp. AmelKG-AP SID8374 S04 S. sp. SID2119 Here, we systematically examine our hypothesis that insect S. sp. ScaeMP-e10 SID5594 S. sp. Wigar10 SID4944 S05 S. sp. CcalMP-8W SID8356 microbiomes are a valuable source of new antimicrobials. The S. sp. SolWspMP-sol2th SID8359 S06 n =98 S. sp. AmelKG-D3 SID8350 S. sp. SA3 actG SID4926 extreme diversity of insects presents untapped potential for drug n = 227 e S. sp. HrubLS-53 SID8380 S07 S. sp. LcepLS SID4945 S. sp. ScaeMP-6W SID4934 discovery from their equally diverse microbial communities. n = 208 S. sp. LaPpAH-201 SID8370 S. sp. LaPpAH-202 SID8371 C-II S08 S. sp. BvitLS-983 SID4915 n =11 S. albus J1074 SID7817 However, the breadth of natural product biosynthesis and anti- S09 S. sp. E114 SID8385 n =37 S10 S. chartreusis NRRL 12338 SID5464 microbial potential within insect microbiomes remains relatively f S. sp. SID5643 Free-living n =46 S. virens NRRL B-24331 SID7804 S11 S. sp. SID4956 unknown. We hypothesize that Streptomyces from insect micro- n =91 S. sp. FxanaD5 SID8376 Insect- S. sp. AmelKG-F2B SID8352 S12 S. sp. SID5910 associated n =86 S. sp. SID5606 biomes represent a promising source of
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