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Emerging evolutionary paradigms in antibiotic discovery

  • Natural Products - Original Paper
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Journal of Industrial Microbiology & Biotechnology

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Abstract

Antibiotics revolutionized medicine and remain its cornerstone. Despite their global importance and the continuous threat of resistant pathogens, few antibiotics have been discovered in recent years. Natural products, especially the secondary metabolites of Actinobacteria, have been the traditional discovery source of antibiotics. In nature, the chemistry of antibiotic natural products is shaped by the unique evolution and ecology of their producing organisms, yet these influences remain largely unknown. Here, we highlight the ecology of antibiotics employed by microbes in defensive symbioses and review the evolutionary processes underlying the chemical diversity and activity of microbe-derived antibiotics, including the dynamics of vertical and lateral transmission of biosynthetic pathways and the evolution of efficacy, targeting specificity, and toxicity. We argue that a deeper understanding of the ecology and evolution of microbial interactions and the metabolites that mediate them will allow for an alternative, rational approach to discover new antibiotics.

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References

  1. Abdelmohsen UR, Grkovic T, Balasubramanian S, Kamel MS, Quinn RJ, Hentschel U (2015) Elicitation of secondary metabolism in actinomycetes. Biotechnol Adv 33:798–811

    Article  CAS  PubMed  Google Scholar 

  2. Adnani N, Chevrette MG, Adibhatla SN, Zhang F, Yu Q, Braun DR, Nelson J, Simpkins SW, McDonald BR, Myers CL, Piotrowski JS, Thompson CJ, Currie CR, Li L, Rajski SR, Bugni TS (2017) Coculture of marine invertebrate-associated bacteria and interdisciplinary technologies enable biosynthesis and discovery of a new antibiotic, keyicin. ACS Chem Biol 12:3093–3102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Baltz RH (2005) Antibiotic discovery from actinomycetes: will a renaissance follow the decline and fall? SIMB News 55:186–196

    Google Scholar 

  4. Baltz RH (2006) Marcel faber roundtable: is our antibiotic pipeline unproductive because of starvation, constipation or lack of inspiration? J Ind Microbiol Biotechnol 33:507–513

    Article  CAS  PubMed  Google Scholar 

  5. Baltz RH (2014) Combinatorial biosynthesis of cyclic lipopeptide antibiotics: a model for synthetic biology to accelerate the evolution of secondary metabolite biosynthetic pathways. ACS Synth Biol 3:748–758

    Article  CAS  PubMed  Google Scholar 

  6. Baltz RH (2018) Synthetic biology, genome mining, and combinatorial biosynthesis of nrps-derived antibiotics: a perspective. J Ind Microbiol Biotechnol 45:635–649

    Article  CAS  PubMed  Google Scholar 

  7. Baltz RH (2008) Renaissance in antibacterial discovery from actinomycetes. Curr Opin Pharmacol 8:557–563

    Article  CAS  PubMed  Google Scholar 

  8. Bhullar K, Waglechner N, Pawlowski A, Koteva K, Banks ED, Johnston MD, Barton HA, Wright GD (2012) Antibiotic resistance is prevalent in an isolated cave microbiome. PLoS One 7:1–11

    Article  CAS  Google Scholar 

  9. Blin K, Wolf T, Chevrette MG, Lu X, Schwalen CJ, Kautsar SA, Suarez Duran HG, de los Santos ELC, Kim HU, Nave M, Dickschat JS, Mitchell DA, Shelest E, Breitling R, Takano E, Lee SY, Weber T, Medema MH (2017) AntiSMASH 4.0—improvements in chemistry prediction and gene cluster boundary identification. Nucleic Acids Res 1854:1019–1037

    Google Scholar 

  10. Blodgett JAV, Oh D-C, Cao S, Currie CR, Kolter R, Clardy J (2010) Common biosynthetic origins for polycyclic tetramate macrolactams from phylogenetically diverse bacteria. Proc Natl Acad Sci 107:11692–11697

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bologa CG, Ursu O, Oprea TI, Melançon CE, Tegos GP (2013) Emerging trends in the discovery of natural product antibacterials. Curr Opin Pharmacol 13:678–687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, Scheld M, Spellberg B, Bartlett J (2009) Bad bugs, no drugs: no eskape! an update from the infectious diseases society of america. Clin Infect Dis 48:1–12

    Article  PubMed  Google Scholar 

  13. Brown ED, Wright GD (2016) Antibacterial drug discovery in the resistance era. Nature 529:336–343

    Article  CAS  PubMed  Google Scholar 

  14. Brucker RM, Harris RN, Schwantes CR, Gallaher TN, Flaherty DC, Lam BA, Minbiole KPCC (2008) Amphibian chemical defense: antifungal metabolites of the microsymbiont Janthinobacterium lividum on the salamander Plethodon cinereus. J Chem Ecol 34:1422–1429

    Article  CAS  PubMed  Google Scholar 

  15. Buchfink B, Xie C, Huson DH (2015) Fast and sensitive protein alignment using diamond. Nat Methods 12:59–60

    Article  CAS  PubMed  Google Scholar 

  16. Caetano-Anollés G, Yafremava LS, Gee H, Caetano-Anollés D, Kim HS, Mittenthal JE (2009) The origin and evolution of modern metabolism. Int J Biochem Cell Biol 41:285–297

    Article  CAS  PubMed  Google Scholar 

  17. Cafaro MJ, Poulsen M, Little AEF, Price SL, Gerardo NM, Wong B, Stuart AE, Larget B, Abbot P, Currie CR (2011) Specificity in the symbiotic association between fungus-growing ants and protective Pseudonocardia bacteria. Proc Biol Sci 278:1814–1822

    Article  PubMed  Google Scholar 

  18. Cai W, Zhang W (2018) Engineering modular polyketide synthases for production of biofuels and industrial chemicals. Curr Opin Biotechnol 50:32–38

    Article  CAS  PubMed  Google Scholar 

  19. Caldera EJ, Currie CR (2012) The population structure of antibiotic-producing bacterial symbionts of Apterostigma dentigerum ants: impacts of coevolution and multipartite symbiosis. Am Nat 180:604–617

    Article  PubMed  PubMed Central  Google Scholar 

  20. Carr G, Derbyshire ER, Caldera E, Currie CR, Clardy J (2012) Antibiotic and antimalarial quinones from fungus-growing ant-associated Pseudonocardia sp. J Nat Prod 75:1806–1809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Challis GL, Hopwood Da (2003) Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species. Proc Natl Acad Sci 100(Suppl):14555–14561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chapela IH, Rehner SA, Schultz TR, Mueller UG (1994) Evolutionary history of the symbiosis between fungus-growing ants and their fungi. Science 266:1691–1694

    Article  CAS  PubMed  Google Scholar 

  23. Chevrette MG, Aicheler F, Kohlbacher O, Currie CR, Medema MH (2017) SANDPUMA: ensemble predictions of nonribosomal peptide chemistry reveal biosynthetic diversity across actinobacteria. Bioinformatics 33:3202–3210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Clardy J, Fischbach Ma, Currie CR (2009) The natural history of antibiotics. Curr Biol 19:1–8

    Article  CAS  Google Scholar 

  25. Cox G, Wright GD (2013) Intrinsic antibiotic resistance: mechanisms, origins, challenges and solutions. Int J Med Microbiol 303:287–292

    Article  CAS  PubMed  Google Scholar 

  26. Crüsemann M, Kohlhaas C, Piel J (2013) Evolution-guided engineering of nonribosomal peptide synthetase adenylation domains. Chem Sci 4:1041

    Article  Google Scholar 

  27. Cruz-Morales P, Kopp JF, Martínez-Guerrero C, Yáñez-Guerra LA, Selem-Mojica N, Ramos-Aboites H, Feldmann J, Barona-Gómez F (2016) Phylogenomic analysis of natural products biosynthetic gene clusters allows discovery of arseno-organic metabolites in model streptomycetes. Genome Biol Evol 8:1906–1916

    Article  PubMed  PubMed Central  Google Scholar 

  28. Currie CR, Bot ANM, Boomsma JJ (2003) Experimental evidence of a tripartite mutualism: bacteria protect ant fungus gardens from specialized parasites. Oikos 101:91–102

    Article  Google Scholar 

  29. Currie CR (2001) A community of ants, fungi, and bacteria: a multilateral approach to studying symbiosis. Annu Rev Microbiol 55:357–380

    Article  CAS  PubMed  Google Scholar 

  30. Currie CR, Scott Ja, Summerbell RC, Malloch D (1999) Fungus-growing ants use antibiotic-producing bacteria to control garden parasites. Nature 398:701–704

    Article  CAS  Google Scholar 

  31. Currie CR, Poulsen M, Mendenhall J, Boomsma JJ, Billen J (2006) Coevolved crypts and exocrine glands support mutualistic bacteria in fungus-growing ants. Science 311:81–83

    Article  CAS  PubMed  Google Scholar 

  32. Currie CR, Wong B, Stuart AE, Schultz TR, Rehner Sa, Mueller UG, Sung G-H, Spatafora JW, Straus Na (2003) Ancient tripartite coevolution in the attine ant-microbe symbiosis. Science 299:386–388

    Article  CAS  PubMed  Google Scholar 

  33. D’Costa VM, King CE, Kalan L, Morar M, Sung WWL, Schwarz C, Froese D, Zazula G, Calmels F, Debruyne R, Golding GB, Poinar HN, Wright GD (2011) Antibiotic resistance is ancient. Nature 477:457–461

    Article  CAS  PubMed  Google Scholar 

  34. Davies J (1990) What are antibiotics? Archaic functions for modern activities. Mol Microbiol 4:1227–1232

    Article  CAS  PubMed  Google Scholar 

  35. Davies J (2006) Are antibiotics naturally antibiotics? J Ind Microbiol Biotechnol 33:496–499

    Article  CAS  PubMed  Google Scholar 

  36. Derewacz DK, Covington BC, McLean JA, Bachmann BO (2015) Mapping microbial response metabolomes for induced natural product discovery. ACS Chem Biol. https://doi.org/10.1021/acschembio.5b00001

    Article  PubMed  PubMed Central  Google Scholar 

  37. Doege TC (1965) Tuberculosis mortality in the united states, 1900 to 1960. JAMA J Am Med Assoc 192:1045

    Article  CAS  Google Scholar 

  38. Donia MS, Cimermancic P, Schulze CJ, Wieland Brown LC, Martin J, Mitreva M, Clardy J, Linington RG, Fischbach MA (2014) A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics. Cell 158:1402–1414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Donia MS, Hathaway BJ, Sudek S, Haygood MG, Rosovitz MJ, Ravel J, Schmidt EW (2006) Natural combinatorial peptide libraries in cyanobacterial symbionts of marine ascidians. Nat Chem Biol 2:729–735

    Article  CAS  PubMed  Google Scholar 

  40. Doroghazi JR, Albright JC, Goering AW, Ju K-S, Haines RR, Tchalukov Ka, Labeda DP, Kelleher NL, Metcalf WW (2014) A roadmap for natural product discovery based on large-scale genomics and metabolomics. Nat Chem Biol 10:963–968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Duke SO, Powles SB (2008) Glyphosate: a once-in-a-century herbicide. Pest Manag Sci 64:319–325

    Article  CAS  PubMed  Google Scholar 

  42. Dunn BJ, Khosla C (2013) Engineering the acyltransferase substrate specificity of assembly line polyketide synthases. J R Soc Interface 10:20130297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Eddy SR (2011) Accelerated profile hmm searches. PLoS Comput Biol 7:e1002195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Fajardo A, Martínez JL (2008) Antibiotics as signals that trigger specific bacterial responses. Curr Opin Microbiol 11:161–167

    Article  CAS  PubMed  Google Scholar 

  45. Fischbach M, Walsh C (2006) Assembly-line enzymology for polyketide and nonribosomal peptide antibiotics: logic, machinery, and mechanisms. Chem Rev 5:3468–3496

    Article  CAS  Google Scholar 

  46. Fischbach MA, Walsh CT (2009) Antibiotics for emerging pathogens. Science 325:1089–1093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fischbach Ma, Walsh CT, Clardy J (2008) The evolution of gene collectives: how natural selection drives chemical innovation. Proc Natl Acad Sci 105:4601–4608

    Article  PubMed  PubMed Central  Google Scholar 

  48. Fisher MC, Hawkins NJ, Sanglard D, Gurr SJ (2018) Worldwide emergence of resistance to antifungal drugs challenges human health and food security. Science 360:739–742

    Article  CAS  PubMed  Google Scholar 

  49. Flórez LV, Biedermann PHW, Engl T, Kaltenpoth M (2015) Defensive symbioses of animals with prokaryotic and eukaryotic microorganisms. Nat Prod Rep 32:904–936

    Article  PubMed  Google Scholar 

  50. Gemperline E, Horn HA, Delaney K, Currie CR, Li L (2017) Imaging with mass spectrometry of bacteria on the exoskeleton of fungus-growing ants. ACS Chem Biol 12:1980–1985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ginolhac A, Jarrin C, Robe P, Perrière G, Vogel TM, Simonet P, Nalin R (2005) Type I polyketide synthases may have evolved through horizontal gene transfer. J Mol Evol 60:716–725

    Article  CAS  PubMed  Google Scholar 

  52. Girt GC, Mahindra A, Al Jabri ZJH, De Ste Croix M, Oggioni MR, Jamieson AG (2018) Lipopeptidomimetics derived from teixobactin have potent antibacterial activity against Staphylococcus aureus. Chem Commun 54:2767–2770

    Article  CAS  Google Scholar 

  53. Goettler W, Kaltenpoth M, Herzner G, Strohm E (2007) Morphology and ultrastructure of a bacteria cultivation organ: the antennal glands of female european beewolves, philanthus triangulum (hymenoptera, crabronidae). Arthropod Struct Dev 36:1–9

    Article  PubMed  Google Scholar 

  54. Goh E-B, Yim G, Tsui W, McClure J, Surette MG, Davies J (2002) Transcriptional modulation of bacterial gene expression by subinhibitory concentrations of antibiotics. Proc Natl Acad Sci 99:17025–17030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Helfrich EJN, Piel J (2016) Biosynthesis of polyketides by trans-at polyketide synthases. Nat Prod Rep 27:996–1047

    Google Scholar 

  56. Hertweck C (2015) Decoding and reprogramming complex polyketide assembly lines: prospects for synthetic biology. Trends Biochem Sci. https://doi.org/10.1016/j.tibs.2015.02.001

    Article  PubMed  Google Scholar 

  57. Hochmuth T, Piel J (2009) Polyketide synthases of bacterial symbionts in sponges—evolution-based applications in natural products research. Phytochemistry 70:1841–1849

    Article  CAS  PubMed  Google Scholar 

  58. Hoefler BC, Stubbendieck RM, Josyula NK, Moisan SM, Schulze EM, Straight PD (2017) A link between linearmycin biosynthesis and extracellular vesicle genesis connects specialized metabolism and bacterial membrane physiology. Cell Chem Biol 24(1238–1249):e7

    Google Scholar 

  59. Hopwood DA (2007) Streptomyces in nature and medicine: the antibiotic makers. Oxford University Press, Oxford

    Google Scholar 

  60. Hyatt D, Chen G-L, Locascio PF, Land ML, Larimer FW, Hauser LJ (2010) Prodigal: prokaryotic gene recognition and translation initiation site identification. BMC Bioinform 11:119

    Article  CAS  Google Scholar 

  61. Jenke-Kodama H, Dittmann E (2009) Evolution of metabolic diversity: insights from microbial polyketide synthases. Phytochemistry 70:1858–1866

    Article  CAS  PubMed  Google Scholar 

  62. Jones KE, Patel NG, Levy MA, Storeygard A, Balk D, Gittleman JL, Daszak P (2008) Global trends in emerging infectious diseases. Nature 451:990–993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kakule TB, Lin Z, Schmidt EW (2014) Combinatorialization of fungal polyketide synthase-peptide synthetase hybrid proteins. J Am Chem Soc 136:17882–17890

    Article  CAS  PubMed  Google Scholar 

  64. Kaltenpoth M, Göttler W, Herzner G, Strohm E (2005) Symbiotic bacteria protect wasp larvae from fungal infestation. Curr Biol 15:475–479

    Article  CAS  PubMed  Google Scholar 

  65. Katoh K, Standley DM (2013) MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol Biol Evol 30:772–780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Katz L, Baltz RH (2016) Natural product discovery: past, present, and future. J Ind Microbiol Biotechnol. https://doi.org/10.1007/s10295-015-1723-5

    Article  PubMed  Google Scholar 

  67. Khayatt BI, Overmars L, Siezen RJ, Francke C (2013) Classification of the adenylation and acyl-transferase activity of nrps and pks systems using ensembles of substrate specific hidden markov models. PLoS One 8:e62136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kingston W (2008) Irish contributions to the origins of antibiotics. Ir J Med Sci 177:87–92

    Article  CAS  PubMed  Google Scholar 

  69. Klein EY, Van Boeckel TP, Martinez EM, Pant S, Gandra S, Levin SA, Goossens H, Laxminarayan R (2018) Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc Natl Acad Sci 115:201717295

    Article  CAS  Google Scholar 

  70. Krasilnikov NA (1960) The biological role of microbes-antagonists, producers of antibiotic substances. Soil Sci Plant Nutr 5:184–193

    Article  Google Scholar 

  71. Kroiss J, Kaltenpoth M, Schneider B, Schwinger M-G, Hertweck C, Maddula RK, Strohm E, Svatoš A (2010) Symbiotic streptomycetes provide antibiotic combination prophylaxis for wasp offspring. Nat Chem Biol 6:261–263

    Article  CAS  PubMed  Google Scholar 

  72. Laniado-Laborín R, Cabrales-Vargas MN (2009) Amphotericin b: side effects and toxicity. Rev Iberoam Micol 26:223–227

    Article  PubMed  Google Scholar 

  73. Lewin GR, Carlos C, Chevrette MG, Horn HA, McDonald BR, Stankey RJ, Fox BG, Currie CR (2016) Evolution and ecology of actinobacteria and their bioenergy applications. Annu Rev Microbiol 70:235–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Linares JF, Gustafsson I, Baquero F, Martinez JL (2006) Antibiotics as intermicrobial signaling agents instead of weapons. Proc Natl Acad Sci 103:19484–19489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, Mueller A, Schäberle TF, Hughes DE, Epstein S, Jones M, Lazarides L, Steadman VA, Cohen DR, Felix CR, Fetterman KA, Millett WP, Nitti AG, Zullo AM, Chen C, Lewis K (2015) A new antibiotic kills pathogens without detectable resistance. Nature 517:455–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Little AEF, Currie CR (2008) Black yeast symbionts compromise the efficiency of antibiotic defenses in fungus-growing ants. Ecology 89:1216–1222

    Article  PubMed  Google Scholar 

  77. Liu Y, Kyle S, Straight PD (2018) Antibiotic stimulation of a Bacillus subtilis migratory response. mSphere 3:e00586-17

    Article  PubMed  PubMed Central  Google Scholar 

  78. Liu Z, Wang W, Zhu Y, Gong Q, Yu W, Lu X (2013) Antibiotics at subinhibitory concentrations improve the quorum sensing behavior of chromobacterium violaceum. FEMS Microbiol Lett 341:37–44

    Article  CAS  PubMed  Google Scholar 

  79. Loudon AH, Holland JA, Umile TP, Burzynski EA, Minbiole KPC, Harris RN (2014) Interactions between amphibians’ symbiotic bacteria cause the production of emergent anti-fungal metabolites. Front Microbiol 5:1–8

    Article  Google Scholar 

  80. Martín-Vivaldi M, Peña A, Peralta-Sánchez JM, Sánchez L, Ananou S, Ruiz-Rodríguez M, Soler JJ (2010) Antimicrobial chemicals in hoopoe preen secretions are produced by symbiotic bacteria. Proc R Soc B Biol Sci 277:123–130

    Article  CAS  Google Scholar 

  81. Martín-Vivaldi M, Soler JJ, Peralta-Sánchez JM, Arco L, Martín-Platero AM, Martínez-Bueno M, Ruiz-Rodríguez M, Valdivia E (2014) Special structures of hoopoe eggshells enhance the adhesion of symbiont-carrying uropygial secretion that increase hatching success. J Anim Ecol 83:1289–1301

    Article  PubMed  Google Scholar 

  82. McAlpine JB, Bachmann BO, Piraee M, Tremblay S, Alarco AM, Zazopoulos E, Farnet CM (2005) Microbial genomics as a guide to drug discovery and structural elucidation: eco-02301, a novel antifungal agent, as an example. J Nat Prod 68:493–496

    Article  CAS  PubMed  Google Scholar 

  83. McDonald BR, Currie CR (2017) Lateral gene transfer dynamics in the ancient bacterial genus Streptomyces. MBio 8:e00644-17

    Article  PubMed  PubMed Central  Google Scholar 

  84. Medema MH, Cimermancic P, Sali A, Takano E, Fischbach MA (2014) A systematic computational analysis of biosynthetic gene cluster evolution: lessons for engineering biosynthesis. PLoS Comput Biol 10:e1004016

    Article  PubMed  PubMed Central  Google Scholar 

  85. Medema MH, Fischbach Ma (2015) Computational approaches to natural product discovery. Nat Chem Biol 11:639–648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Medema MH, Kottmann R, Yilmaz P, Cummings M, Biggins JB, Blin K, de Bruijn I, Chooi YH, Claesen J, Coates RC, Cruz-Morales P, Duddela S, Düsterhus S, Edwards DJ, Fewer DP, Garg N, Geiger C, Gomez-Escribano JP, Greule A, Hadjithomas M, Haines AS, Helfrich EJN, Hillwig ML, Ishida K, Jones AC, Jones CS, Jungmann K, Kegler C, Kim HU, Kötter P, Krug D, Masschelein J, Melnik AV, Mantovani SM, Monroe EA, Moore M, Moss N, Nützmann H-W, Pan G, Pati A, Petras D, Reen FJ, Rosconi F, Rui Z, Tian Z, Tobias NJ, Tsunematsu Y, Wiemann P, Wyckoff E, Yan X, Yim G, Yu F, Xie Y, Aigle B, Apel AK, Balibar CJ, Balskus EP, Barona-Gómez F, Bechthold A, Bode HB, Borriss R, Brady SF, Brakhage AA, Caffrey P, Cheng Y-Q, Clardy J, Cox RJ, De Mot R, Donadio S, Donia MS, van der Donk WA, Dorrestein PC, Doyle S, Driessen AJM, Ehling-Schulz M, Entian K-D, Fischbach MA, Gerwick L, Gerwick WH, Gross H, Gust B, Hertweck C, Höfte M, Jensen SE, Ju J, Katz L, Kaysser L, Klassen JL, Keller NP, Kormanec J, Kuipers OP, Kuzuyama T, Kyrpides NC, Kwon H-J, Lautru S, Lavigne R, Lee CY, Linquan B, Liu X, Liu W, Luzhetskyy A, Mahmud T, Mast Y, Méndez C, Metsä-Ketelä M, Micklefield J, Mitchell DA, Moore BS, Moreira LM, Müller R, Neilan BA, Nett M, Nielsen J, O’Gara F, Oikawa H, Osbourn A, Osburne MS, Ostash B, Payne SM, Pernodet J-L, Petricek M, Piel J, Ploux O, Raaijmakers JM, Salas JA, Schmitt EK, Scott B, Seipke RF, Shen B, Sherman DH, Sivonen K, Smanski MJ, Sosio M, Stegmann E, Süssmuth RD, Tahlan K, Thomas CM, Tang Y, Truman AW, Viaud M, Walton JD, Walsh CT, Weber T, van Wezel GP, Wilkinson B, Willey JM, Wohlleben W, Wright GD, Ziemert N, Zhang C, Zotchev SB, Breitling R, Takano E, Glöckner FO (2015) Minimum information about a biosynthetic gene cluster. Nat Chem Biol 11:625–631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Metsä-Ketelä M, Halo L, Munukka E, Hakala J, Mäntsäla P, Ylihonko K (2002) Molecular evolution of aromatic polyketides and comparative sequence analysis of polyketide ketosynthase and 16 s ribosomal dna genes from various Streptomyces species. Appl Environ Microbiol 68:4472–4479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Miller I, Chevrette M, Kwan J (2017) Interpreting microbial biosynthesis in the genomic age: biological and practical considerations. Mar Drugs 15:165

    Article  CAS  PubMed Central  Google Scholar 

  89. Miller IJ, Vanee N, Fong SS, Lim-Fong GE, Kwan JC (2016) Lack of overt genome reduction in the bryostatin-producing bryozoan symbiont, “candidatus endobugula sertula”. Appl Environ Microbiol 82:01800–01816

    Google Scholar 

  90. Mirarab S, Reaz R, Bayzid MS, Zimmermann TS, Swenson M, Warnow T (2014) ASTRAL: genome-scale coalescent-based species tree estimation. Bioinformatics 30:541–548

    Article  CAS  Google Scholar 

  91. Morita M, Schmidt EW (2018) Parallel lives of symbionts and hosts: chemical mutualism in marine animals. Nat Prod Rep 00:1–22

    Google Scholar 

  92. Mousa WK, Athar B, Merwin NJ, Magarvey NA (2017) Antibiotics and specialized metabolites from the human microbiota. Nat Prod Rep 34:1302–1331

    Article  CAS  PubMed  Google Scholar 

  93. Myers JP, Antoniou MN, Blumberg B, Carroll L, Colborn T, Everett LG, Hansen M, Landrigan PJ, Lanphear BP, Mesnage R, Vandenberg LN, Vom Saal FS, Welshons WV, Benbrook CM (2016) Concerns over use of glyphosate-based herbicides and risks associated with exposures: a consensus statement. Environ Heal A Glob Access Sci Source 15:1–13

    Google Scholar 

  94. Nett JE, Andes DR (2016) Antifungal agents: spectrum of activity, pharmacology, and clinical indications. Infect Dis Clin N Am 30:51–83

    Article  Google Scholar 

  95. Newman DJ, Cragg GM (2016) Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 79:629–661

    Article  CAS  PubMed  Google Scholar 

  96. Ng V, Kuehne SA, Chan WC (2018) Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa. Chem A Eur J 24:9136–9147

    Article  CAS  Google Scholar 

  97. Nguyen DD, Melnik AV, Koyama N, Lu X, Schorn M, Fang J, Aguinaldo K, Lincecum TL, Ghequire MGK, Carrion VJ, Cheng TL, Duggan BM, Malone JG, Mauchline TH, Sanchez LM, Kilpatrick AM, Raaijmakers JM, De Mot R, Moore BS, Medema MH, Dorrestein PC (2016) Indexing the Pseudomonas specialized metabolome enabled the discovery of poaeamide b and the bananamides. Nat Microbiol 2:16197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. O’Neill J (2016) Tackling drug-resistant infections globally: final report and recommendations. Review on antimicrobial resistance. Wellcome Trust and the UK Department of Health. https://amr-review.org/sites/default/files/160525_Final%20paper_with%20cover.pdf. Accessed 1 Sept 2018

  99. Oh D-C, Poulsen M, Currie CR, Clardy J (2009) Dentigerumycin: a bacterial mediator of an ant-fungus symbiosis. Nat Chem Biol 5:391–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Pagel M (1994) Detecting correlated evolution on phylogenies: a general method for the comparative analysis of discrete characters. Proc Biol Sci 255:37–45

    Article  Google Scholar 

  101. Parmar A, Lakshminarayanan R, Iyer A, Mayandi V, Leng Goh ET, Lloyd DG, Chalasani MLS, Verma NK, Prior SH, Beuerman RW, Madder A, Taylor EJ, Singh I (2018) Design and syntheses of highly potent teixobactin analogues against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (mrsa), and vancomycin-resistant Enterococci (vre) in vitro and in vivo. J Med Chem 61:2009–2017

    Article  CAS  PubMed  Google Scholar 

  102. Patridge E, Gareiss P, Kinch MS, Hoyer D (2016) An analysis of fda-approved drugs: natural products and their derivatives. Drug Discov Today 21:204–207

    Article  CAS  PubMed  Google Scholar 

  103. Pendleton JN, Gorman SP, Gilmore BF (2013) Clinical relevance of the eskape pathogens. Expert Rev Anti Infect Ther 11:297–308

    Article  CAS  PubMed  Google Scholar 

  104. Penn K, Jenkins C, Nett M, Udwary DW, Gontang EA, McGlinchey RP, Foster B, Lapidus A, Podell S, Allen EE, Moore BS, Jensen PR (2009) Genomic islands link secondary metabolism to functional adaptation in marine actinobacteria. ISME J 3:1193–1203

    Article  CAS  PubMed  Google Scholar 

  105. Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A (2017) The global problem of antifungal resistance: prevalence, mechanisms, and management. Lancet Infect Dis 17:e383–e392

    Article  PubMed  Google Scholar 

  106. Poulsen M, Cafaro MJ, Erhardt DP, Little AEF, Gerardo NM, Tebbets B, Klein BS, Currie CR (2010) Variation in Pseudonocardia antibiotic defence helps govern parasite-induced morbidity in acromyrmex leaf-cutting ants. Environ Microbiol Rep 2:534–540

    Article  CAS  PubMed  Google Scholar 

  107. Price MN, Dehal PS, Arkin AP (2010) FastTree 2—approximately maximum-likelihood trees for large alignments. PLoS One 5:e9490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Pye CR, Bertin MJ, Lokey RS, Gerwick WH, Linington RG (2017) Retrospective analysis of natural products provides insights for future discovery trends. Proc Natl Acad Sci 114:5601–5606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Rateb ME, Zhai Y, Ehrner E, Rath CM, Wang X, Tabudravu J, Ebel R, Bibb M, Kyeremeh K, Dorrestein PC, Hong K, Jaspars M, Deng H (2015) Legonaridin, a new member of linaridin ripp from a ghanaian Streptomyces isolate. Org Biomol Chem. https://doi.org/10.1039/C5OB01269D

    Article  PubMed  Google Scholar 

  110. Rausch C, Hoof I, Weber T, Wohlleben W, Huson DH (2007) Phylogenetic analysis of condensation domains in nrps sheds light on their functional evolution. BMC Evol Biol 7:78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ream DC, Bankapur AR, Friedberg I (2015) An event-driven approach for studying gene block evolution in bacteria. Bioinformatics. https://doi.org/10.1093/bioinformatics/btv128

    Article  PubMed  PubMed Central  Google Scholar 

  112. Ridley CP, Lee HY, Khosla C (2008) Evolution of polyketide synthases in bacteria. Proc Natl Acad Sci 105:4595–4600

    Article  PubMed  PubMed Central  Google Scholar 

  113. Romero D, Traxler MF, López D, Kolter R (2011) Antibiotics as signal molecules. Chem Rev 111:5492–5505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Rounge TB, Rohrlack T, Kristensen T, Jakobsen KS (2008) Recombination and selectional forces in cyanopeptolin nrps operons from highly similar, but geographically remote planktothrix strains. BMC Microbiol 8:141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Ruiz-Rodríguez M, Martínez-Bueno M, Martín-Vivaldi M, Valdivia E, Soler JJ (2013) Bacteriocins with a broader antimicrobial spectrum prevail in enterococcal symbionts isolated from the hoopoe’s uropygial gland. FEMS Microbiol Ecol 85:495–502

    Article  CAS  PubMed  Google Scholar 

  116. Sardar D, Pierce E, McIntosh JA, Schmidt EW (2015) Recognition sequences and substrate evolution in cyanobactin biosynthesis. ACS Synth Biol 4:167–176

    Article  CAS  PubMed  Google Scholar 

  117. Scott JJ, Oh D-C, Yuceer MC, Klepzig KD, Clardy J, Currie CR (2008) Bacterial protection of beetle-fungus mutualism. Science 322:63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Shapiro BJ, Friedman J, Cordero OX, Preheim SP, Timberlake SC, Szabo G, Polz MF, Alm EJ (2012) Population genomics of early events in the ecological differentiation of bacteria. Science 336:48–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Shapiro BJ (2014) Adv Exp Med Biol 781:339–359

    Article  CAS  PubMed  Google Scholar 

  120. Sit CS, Ruzzini AC, Van Arnam EB, Ramadhar TR, Currie CR, Clardy J (2015) Variable genetic architectures produce virtually identical molecules in bacterial symbionts of fungus-growing ants. Proc Natl Acad Sci. https://doi.org/10.1073/pnas.1515348112

    Article  PubMed  PubMed Central  Google Scholar 

  121. Smanski MJ, Bhatia S, Zhao D, Park Y, Woodruff LBA, Giannoukos G, Ciulla D, Busby M, Calderon J, Nicol R, Gordon DB, Densmore D, Voigt CA (2014) Functional optimization of gene clusters by combinatorial design and assembly. Nat Biotechnol 32:1241–1249

    Article  CAS  PubMed  Google Scholar 

  122. Smith PA, Koehler MFT, Girgis HS, Yan D, Chen Y, Chen Y, Crawford JJ, Durk MR, Higuchi RI, Kang J, Murray J, Paraselli P, Park S, Phung W, Quinn JG, Roberts TC, Rougé L, Schwarz JB, Skippington E, Wai J, Xu M, Yu Z, Zhang H, Tan M-W, Heise CE (2018) Optimized arylomycins are a new class of gram-negative antibiotics. Nature 561:189–194

    Article  CAS  PubMed  Google Scholar 

  123. Soler JJ, Martín-Vivaldi M, Ruiz-Rodríguez M, Valdivia E, Martín-Platero AM, Martínez-Bueno M, Peralta-Sánchez JM, Méndez M (2008) Symbiotic association between hoopoes and antibiotic-producing bacteria that live in their uropygial gland. Funct Ecol 22:864–871

    Article  Google Scholar 

  124. Sprenger M, Fukuda K (2016) New mechanisms, new worries. Science 351:1263–1264

    Article  CAS  PubMed  Google Scholar 

  125. Stamatakis A (2014) RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics 30:1312–1313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Stubbendieck RM, Straight PD (2016) Multifaceted interfaces of bacterial competition. J Bacteriol JB. https://doi.org/10.1128/jb.00275-16

    Article  Google Scholar 

  127. Surette M, Wright GD (2017) Lessons from the environmental antibiotic resistome. Annu Rev Microbiol. https://doi.org/10.1146/annurev-micro-090816-093420

    Article  PubMed  Google Scholar 

  128. Traxler MF, Kolter R (2015) Natural products in soil microbe interactions and evolution. Nat Prod Rep 00:1–15

    Google Scholar 

  129. Udwary DW, Zeigler L, Asolkar RN, Singan V, Lapidus A, Fenical W, Jensen PR, Moore BS (2007) Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica. Proc Natl Acad Sci 104:10376–10381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Vagstad AL, Newman AG, Storm PA, Belecki K, Crawford JM, Townsend CA (2013) Combinatorial domain swaps provide insights into the rules of fungal polyketide synthase programming and the rational synthesis of non-native aromatic products. Angew Chem Int Ed Engl 52:1718–1721

    Article  CAS  PubMed  Google Scholar 

  131. VanArnam EB, Currie CR, Clardy J (2017) Defense contracts: molecular protection in insect–microbe symbioses. Chem Soc Rev. https://doi.org/10.1039/C7CS00340D

    Article  Google Scholar 

  132. VanArnam EB, Ruzzini AC, Sit CS, Horn H, Pinto-Tomás AA, Currie CR, Clardy J (2016) Selvamicin, an atypical antifungal polyene from two alternative genomic contexts. Proc Natl Acad Sci 113:12940–12945

    Article  CAS  Google Scholar 

  133. Waksman SA (1949) Origin and nature of antibiotics. Am J Med 7:85–99

    Article  CAS  PubMed  Google Scholar 

  134. Waksman SA (1961) The role of antibiotics in nature. Perspect Biol Med 4:271–287

    Article  Google Scholar 

  135. Winn M, Fyans JK, Zhuo Y, Micklefield J (2016) Recent advances in engineering nonribosomal peptide assembly lines. Nat Prod Rep 33:317–347

    Article  CAS  PubMed  Google Scholar 

  136. Wright GD (2017) Opportunities for natural products in 21st century antibiotic discovery. Nat Prod Rep 34:694–701

    Article  CAS  PubMed  Google Scholar 

  137. Yang X, Van Der Donk WA (2013) Ribosomally synthesized and post-translationally modified peptide natural products: new insights into the role of leader and core peptides during biosynthesis. Chem A Eur J 19:7662–7677

    Article  CAS  Google Scholar 

  138. Yim G, Wang HH, Davies J (2007) Antibiotics as signalling molecules. Philos Trans R Soc B Biol Sci 362:1195–1200

    Article  CAS  Google Scholar 

  139. Yuzawa S, Keasling JD, Katz L (2017) Bio-based production of fuels and industrial chemicals by repurposing antibiotic-producing type I modular polyketide synthases: opportunities and challenges. J Antibiot 70:378–385

    Article  CAS  Google Scholar 

  140. Ziemert N, Lechner A, Wietz M, Millán-Aguiñaga N, Chavarria KL, Jensen PR (2014) Diversity and evolution of secondary metabolism in the marine actinomycete genus Salinispora. Proc Natl Acad Sci 111:E1130–E1139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Zipperer A, Konnerth MC, Laux C, Berscheid A, Janek D, Weidenmaier C, Burian M, Schilling NA, Slavetinsky C, Marschal M, Willmann M, Kalbacher H, Schittek B, Brötz-Oesterhelt H, Grond S, Peschel A, Krismer B (2016) Human commensals producing a novel antibiotic impair pathogen colonization. Nature 535:511–516

    Article  CAS  PubMed  Google Scholar 

  142. Zucko J, Cullum J, Hranueli D, Long PF (2011) Evolutionary dynamics of modular polyketide synthases, with implications for protein design and engineering. J Antibiot 64:89–92

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank Heidi Horn, Reed Stubbendieck, Lily Khadempour, Don Hoang, Jennifer Bratburd, Alex Cheong, Daniel May, and Ian Miller for meaningful discussion and critical appraisal of the manuscript. This project was supported through National Institutes of Health (NIH) U19 Al109673. Additional support was provided to MGC through NIH National Research Service Award T32 GM008505.

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  1. Department of Genetics, University of Wisconsin-Madison, Madison, WI, USA

    Marc G. Chevrette

  2. Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA

    Marc G. Chevrette & Cameron R. Currie

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  1. Marc G. Chevrette
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  2. Cameron R. Currie
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Correspondence to Cameron R. Currie.

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This article is part of the Special Issue “Natural Product Discovery and Development in the Genomic Era 2019”.

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Chevrette, M.G., Currie, C.R. Emerging evolutionary paradigms in antibiotic discovery. J Ind Microbiol Biotechnol 46, 257–271 (2019). https://doi.org/10.1007/s10295-018-2085-6

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