Abstract
Microorganisms have provided abundant sources of natural products which have been developed as commercial products for human medicine, animal health, and plant crop protection. In the early years of natural product discovery from microorganisms (The Golden Age), new antibiotics were found with relative ease from low-throughput fermentation and whole cell screening methods. Later, molecular genetic and medicinal chemistry approaches were applied to modify and improve the activities of important chemical scaffolds, and more sophisticated screening methods were directed at target disease states. In the 1990s, the pharmaceutical industry moved to high-throughput screening of synthetic chemical libraries against many potential therapeutic targets, including new targets identified from the human genome sequencing project, largely to the exclusion of natural products, and discovery rates dropped dramatically. Nonetheless, natural products continued to provide key scaffolds for drug development. In the current millennium, it was discovered from genome sequencing that microbes with large genomes have the capacity to produce about ten times as many secondary metabolites as was previously recognized. Indeed, the most gifted actinomycetes have the capacity to produce around 30–50 secondary metabolites. With the precipitous drop in cost for genome sequencing, it is now feasible to sequence thousands of actinomycete genomes to identify the “biosynthetic dark matter” as sources for the discovery of new and novel secondary metabolites. Advances in bioinformatics, mass spectrometry, proteomics, transcriptomics, metabolomics and gene expression are driving the new field of microbial genome mining for applications in natural product discovery and development.
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References
Aigle B, Lautru S, Spiteller D, Dickschat JS, Challis GL, Leblond P, Pernodet JL (2014) Genome mining of Streptomyces ambofaciens. J Ind Microbiol Biotechnol 41:251–264
Alberts AW, Chen J, Kuron G et al (1980) Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-CoA reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA 77:3957–3961
Alexander D, Rock J, He X, Miao V, Brian P, Baltz RH (2010) Development of a genetic system for lipopeptide combinatorial biosynthesis in Streptomyces fradiae and heterologous expression of the A54145 biosynthetic gene cluster. Appl Environ Microbiol 76:6877–6887
Alexander D, Rock J, Gu JQ, Mascio C, Chu M, Brian P, Baltz RH (2011) Production of novel lipopeptide antibiotics related to A54145 by Streptomyces fradiae mutants blocked in biosynthesis of modified amino acids and assignment of lptJ, lptK and lptL gene functions. J Antibiot 64:79–87
Amando SI, Sakurai T, Endo K et al (2011) A cryptic antibiotic triggered by monensin. J Antibiot 64:703
Bachmann BO, Van Lanen SG, Baltz RH (2014) Microbial genome mining for accelerated natural products discovery: is a renaissance in the making? J Ind Microbiol Biotechnol 41:175–184
Baltz RH (1982) Genetics and biochemistry of tylosin production: a model for genetic engineering in antibiotic-producing Streptomyces. Basic Life Sci 19:431–444
Baltz RH (2005) Natural product discovery and development at Eli Lilly and Company: one scientists view. SIM News 55:5–16
Baltz RH (2005) Antibiotic discovery from actinomycetes: will a renaissance follow the decline and fall? SIM News 55:186–196
Baltz RH (2006) Combinatorial biosynthesis of novel antibiotics and other secondary metabolites in actinomycetes. SIM News 56:148–160
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
Baltz RH (2006) Molecular engineering approaches to peptide, polyketide and other antibiotics. Nat Biotechnol 24:1533–1540
Baltz RH (2007) Antimicrobials from actinomycetes: back to the future. Microbe 2:125–131
Baltz RH (2008) Renaissance in antibacterial discovery from actinomycetes. Curr Opin Pharmacol 8:557–563
Baltz RH (2010) Streptomyces and Saccharopolyspora hosts for heterologous expression of secondary metabolite gene clusters. J Ind Microbiol Biotechnol 37:759–772
Baltz RH (2011) Strain improvement in actinomycetes in the postgenomic era. J Ind Microbiol Biotechnol 38:657–666
Baltz RH (2011) Function of MbtH homologs in nonribosomal peptide biosynthesis and applications in secondary metabolite discovery. J Ind Microbiol Biotechnol 38:1747–1760
Baltz RH (2012) Streptomyces temperate bacteriophage integration systems for stable genetic engineering of actinomycetes (and other organisms). J Ind Microbiol Biotechnol 39:661–672
Baltz RH (2014) MbtH homology codes to identify gifted microbes for genome mining. J Ind Microbiol Biotechnol 41:357–369
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 3:748–759
Baltz RH (2015) Genetic manipulation of secondary metabolite biosynthesis for improved production in Streptomyces and other actinomycetes. J Ind Microbiol Biotechnol. doi:10.1007/s10295-015-1682-x
Baltz RH, Seno ET (1981) Properties of Streptomyces fradiae mutants blocked in biosynthesis of the macrolide antibiotic tylosin. Antimicrob Agents Chemother 20:214–225
Baranasic D, Gacesa R, Starcevic A et al (2013) Draft genome sequence of Streptomyces rapamycinicus strain NRRL 5491, the producer of the immunosuppressant rapamycin. Genome Announc 1:e00581–e00613
Bentley SD, Chater KF, Cerdeño-Tárraga AM et al (2002) Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417:141–147
Bérdy J (2012) Thoughts and facts about antibiotics: where we are now and where we are heading. J Antibiot 65:385–395
Bhanot A, Sharma R, Noolvi MN (2011) Natural sources as potential anti-cancer agents: a review. Int J Phytomed 3:9–26
Bibb MJ, Ward JM, Hopwood DA (1978) Transformation of plasmid DNA into Streptomyces at high frequency. Nature 274:398–400
Bierman M, Logan R, O’Brien K, Seno ET, Rao RN, Schoner BE (1992) Plasmid cloning vectors for the conjugal transfer of DNA from Escherichia coli to Streptomyces spp. Gene 116:43–49
Breton RC, Reynolds WF (2013) Using NMR to identify and characterize natural products. Nat Prod Rep 30:501–534
Butler MS, Robertson AA, Cooper MA (2014) Natural product and natural product derived drugs in clinical trials. Nat Prod Rep 31:1612–1661
Challis GL (2014) Exploitation of the Streptomyces coelicolor A3(2) genome sequence for discovery of new natural products and biosynthetic pathways. J Ind Microbiol Biotechnol 41:219–232
Charlop-Powers Z, Owen JG, Reddy BVB, Ternei MA, Guimaraes DO, de Frias UA, Pupo MT, Seepe P, Feng Z, Brady SF (2015) Global biogeographic sampling of bacterial secondary metabolism. eLife 4:e05048
Cohen SN, Chang AC, Boyer HW, Helling RB (1973) Construction of biologically functional bacterial plasmids in vitro. Proc Natl Acad Sci USA 70:3240–3244
Cundliffe E (2008) Control of tylosin biosynthesis in Streptomyces fradiae. J Microbiol Biotechnol 18:1485–1491
Debono M, Willard KE, Kirst HA et al (1989) Synthesis and antimicrobial evaluation of 20-deoxo-20-(3,5-dimethylpiperidin-1-yl)desmycosin and related cyclic amino derivatives. J Antibiot 42:1253–1267
Demain AL (2014) Importance of microbial natural products and the need to revitalize their discovery. J Ind Microbiol Biotechnol 41:185–201
Denizot F, Lang R (1986) Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods 89:271–277
Denoya CD, Fedechko RW, Hafner EW et al (1995) A second branched-chain α-keto acid dehydrogenase gene cluster (bkdFGH) from Streptomyces avermitilis: its relationship to avermectin biosynthesis and the construction of a bkdF mutant suitable for the production of novel antiparasitic avermectins. J Bacteriol 177:3504–3511
DiMarco A, Gaetani M, Dorigotti L, Soldati M, Bellini O (1964) Daunomycin: a new antibiotic with anti-tumor activity. Cancer Chemother Rep 38:31–38
Dutta S, Whicher JR, Hansen DA et al (2014) Structure of a modular polyketide synthase. Nature 510:512–517
Eisenstein BI, Oleson FB Jr, Baltz RH (2010) Daptomycin: from the mountain to the clinic with the essential help from Francis Tally, MD. Clin Inf Dis 50:S10–S15
Endo AMK (1979) A new hypo-cholesteremic agent produced by a Monascus species. J Antibiot 32:852–854
Endo A (2010) A historical perspective on the discovery of the statins. Proc Jpn Acad Ser B 86:484–493
Epp JK, Huber ML, Turner JR, Goodson T, Schoner BE (1989) Production of a hybrid macrolide antibiotic in Streptomyces ambofaciens and Streptomyces lividans by introduction of a cloned carbomycin biosynthetic gene from Streptomyces thermotolerans. Gene 85:293–301
Galm U, Sparks TC (2015) Natural product derived insecticides: discovery and development of spinetoram. J Ind Microbiol Biotechnol. doi:10.1007/s10295-015-1710-x
Gallo RC, Whang-Peng J, Adamson RH (1971) Studies on the antitumor activity, mechanism of action, and cell cycle effects of camptothecin. J Nat Cancer Inst 46:789–795
Giddings LA, Newman DJH (2013) Microbial natural products: molecular blueprints for antitumor drugs. J Ind Microbiol Biotechnol 40:1181–1210
Gregory MA, Petkovic H, Lill RE, Moss SJ, Wilkinson B, Gaisser S, Leadlay PF, Sheridan RE (2005) Mutasynthesis of rapamycin analogues through the manipulation of a gene governing starter unit biosynthesis. Angew Chem Int Ed 44:4757–4760
Havlicek V, Lemr K, Schug KA (2013) Current trends in microbial diagnostics based on mass spectrometry. Anal Chem 85:790–797
Heeb S, Fletcher MP, Chhabra SR, Diggle SP, Williams P, Cámara M (2011) Quinolones: from antibiotics to autoinducers. FEMS Microbiol Rev 35:247–274
Heide L (2014) New aminocoumarin antibiotics as gyrase inhibitors. Int J Med Microbiol 304:31–36
Henderson DJ, Naya I, Bundick RV, Smith GM, Schmidt JA (1991) Comparison of the effects of FK-506, cyclosporine A and rapamycin on IL-2 production. Immunology 73:316–321
Hendlin D, Stapley EO, Jackson M et al (1969) Phosphonomycin, a new antibiotic produced by strains of Streptomyces. Science 166:122–123
Hertweck C (2015) Decoding and reprogramming complex polyketide assembly lines: prospects for synthetic biology. Trends Biochem Sci 40:189–199
Heusler K, Pletscher A (2001) The controversial early history of cyclosporine. Swiss Med Wkly 131:299–302
Hur GH, Vickery CR, Burkart MD (2012) Explorations of catalytic domains in non-ribosomal peptide synthetase enzymology. Nat Prod Rep 29:1074–1098
Iftime D, Kylik A, Härtner T et al (2015) Identification and activation of novel biosynthetic gene clusters by genome mining in the kirromycin producer Tü 365. J Ind Microbiol Biotechnol. doi:10.1007/s100295-015-1685-7
Ikeda H, Ishikawas J, Hanamoto A, Shinose M, Kikuchi H, Shiba T, Sakaki Y, Hattori M, Ōmura S (2003) Complete genome sequence of and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat Biotechnol 21:526–531
Ikeda H, Shin-ya K, Omura S (2014) Genome mining of the Streptomyces avermitilis genome and development of genome-minimized hosts for heterologous expression of biosynthetic gene clusters. J Ind Microbiol Biotechnol 41:233–250
Itoh T, Ishii K, Irikura T, Ueno Y, Kojima A, Horie Y (1993) A modified method of mixed lymphocyte reaction: establishment of the assay system and its application to extracts of fungal cultures. J Antibiot 46:1575–1581
Johnston CW, Connaty AD, Skinnider MA, Li Y, Grunwald A, Wyatt MA, Kerr RG, Magarvey NA (2015) Informatic search strategies to discover analogues and variants of natural product archetypes. J Ind Microbiol Biotechnol. doi:10.1007/s10295-015-1675-9
Ju KS, Gao J, Doroghazi JR et al (2015) Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes. Proc Natl Acad Sci USA 112:12175–12180
Kanomori H, Shima T, Morita C, Hata T (1957) Studies on the antitumor activity of mitomycin. J Antibiot 10:120–127
Katz M, Hover BM, Brady SF (2015) Culture-independent discovery of natural products from soil metagenomes. J Ind Microbiol Biotechnol. doi:10.1007/s10295-015-1706-6
Khaw LE, Böhm GA, Metcalf S, Staunton J, Leadlay PF (1998) Mutational biosynthesis of rapamycins by a strain of Streptomyces hygroscopicus NRRL 5491 disrupted in rapL, encoding a putative lysine cyclodeaminase. J Bacteriol 180:89–814
Khosla C, Hershlag D, Cane DE, Walsh CT (2014) Assembly line polyketide synthases: mechanistic insights and unsolved problems. Biochemistry 53:2875–2883
Kim E, Moore BS, Yoon YJ (2015) Reinvigorating natural product combinatorial biosynthesis with synthetic biology. Nat Chem Biol 11:649–659
Kinch MS, Haynesworth A, Kinch SL, Hoyer D (2014) An overview of FDA-approved new molecular entities: 1827–2013. Drug Discov Today 19:1033–1039
Kirst HA (2010) The spinosyn family of insecticides: realizing the potential of natural products research. J Antibiot 63:101–111
Koehn FE, Carter GT (2005) The evolving role of natural products in drug discovery. Nat Rev Drug Discov 4:206–220
Kudo F, Eguchi T (2009) Biosynthesis genes for aminoglycoside antibiotics. J Antibiot 62:471–481
Kustoss S, Huber M, Turner JR, Paschal JW, Rao RN (1996) Production of a novel polyketide through the construction of a hybrid polyketide synthase. Gene 183:231–236
Ladner CC, Williams GJ (2015) Harnessing natural product assembly lines: structure, promiscuity, and engineering. J Ind Microbiol Biotechnol. doi:10.1007/s10295-015-1704-8
Lay M, Ang T, Murima P, Pethe K (2015) Next-generation antimicrobials: from chemical biology to first-in-class drugs. Arch Pharm Res 38:1702–1707
Martel RR, Klicius J, Galet S (1977) Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can J Physiol Pharmacol 55:48–51
Matsushima P, Baltz RH (1985) Efficient plasmid transformation of Streptomyces ambofaciens and Streptomyces fradiae protoplasts. J Bacteriol 163:180–185
McDaniel R, Thamchaipenet A, Gustafsson C, Fu H, Betlach M, Ashley G (1999) Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel “unnatural” natural products. Proc Natl Acad Sci USA 96:1846–1851
Medema MH, Fischbach MA (2015) Computational approaches to natural product discovery. Nat Chem Biol 11:639–648
Milshteyn A, Schneider JS, Brady SF (2014) Mining the metabiome: identifying novel natural products from microbial communities. Chem Biol 21:1211–1223
Minas W, Bailey JE, Duetz W (2000) Streptomycetes in microcultures: growth production of secondary metabolites, and storage and retrieval in the 96 well format. Antonie Van Leeuwenhoek 78:297–305
Moffat JG, Rudolph J, Bailey D (2014) Phenotypic screening in cancer drug discovery—past, present and future. Nat Rev Drug Discov 13:588–602
Mossman T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxic assays. J Immunol Methods 65:55–63
Nagarajan R, Boeck LD, Gorman M, Hamill RL, Higgens CE, Hoehn MM, Stark WM, Whitney JG (1971) β-Lactam antibiotics from Streptomyces. J Am Chem Soc 93:2308–2310
Nett M, Ikeda H, Moore B (2009) Genomic basis for natural product biosynthetic diversity in the actinomycetes. Nat Prod Rep 26:1362–1384
Newman DJ, Cragg GM, Snader KM (2000) The influence of natural products upon drug discovery. Nat Prod Rep 17:214–234
Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75:311–335
Nguyen K, Ritz D, Gu JQ, Alexander D, Chu M, Miao V, Brian P, Baltz RH (2006) Combinatorial biosynthesis of lipopeptide antibiotics related to daptomycin. Proc Natl Acad Sci USA 103:17462–17467
Nguyen KT, He X, Alexander D, Li C, Gu JQ, Mascio C, Van Praagh A, Mortin L, Chu M, Silverman JA, Brian P, Baltz RH (2010) Engineered hybrid lipopeptide antibiotics related to A54145 and daptomycin with improved properties. Antimicrob Agents Chemother 54:1404–1413
Ochi K, Tanaka Y, Tojo S (2014) Activating the expression of bacterial cryptic genes by rpoB mutations in RNA polymerase or by rare earth elements. J Ind Microbiol Biotechnol 41:403–414
Ohnishi Y, Ishikawa J, Hara H, Suzuki H, Ikenoya M, Ikeda H, Yamashita A, Hattori M, Horinouchi S (2008) Genome sequence of the streptomycin-producing microorganism Streptomyces griseus IFO 13350. J Bacteriol 190:4050–4060
Olano C, Méndez C, Salas JA (2010) Post-PKS tailoring steps in natural product-producing actinomycetes from the perspective of combinatorial biosynthesis. Nat Prod Rep 27:571–616
Olano C, Méndez C, Salas JA (2011) Molecular insights on the biosynthesis of antitumor compounds by actinomycetes. Microb Biotechnol 4:144–164
Olynyk M, Brown MJ, Cortés J, Staunton J, Leadlay PF (1996) A hybrid modular polyketide synthase obtained by domain swapping. Chem Biol 3:833–839
Owen JG, Charlop-Powers Z, Smith AG, Ternei MA, Calle PY, Reddy BJB, Montiel D, Brady SF (2015) Multiplexed metagenomic mining using short DNA sequence tags facilitates targeted discovery of epoxyketone proteasome inhibitors. Proc Natl Acad Sci USA 112:4221–4226
Paradkar A (2013) Clavulanic acid production by Streptomyces clavuligerus: biogenesis, regulation and strain improvement. J Antibiot 66:411–420
Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL (2007) Bad drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 6:29–40
Perlman D, Bodanszky D (1971) Biosynthesis of peptide antibiotics. Annu Rev Biochem 40:449–464
Reading C, Cole M (1977) Clavulanic acid: a beta-lactamase-inhibiting beta-lactam from Streptomyces clavuligerus. Antimicrob Agents Chemother 11:852–857
Reeves CD, Ward SL, Revill WP et al (2004) Production of hybrid 16-membered macrolides by expressing combinations of polyketide synthase genes in Streptomyces fradiae hosts. Chem Biol 11:1466–1472
Ruan X, Pereda A, Stassi DL et al (1997) Acyltransferase domain substitutions in erythromycin polyketide synthase yield novel erythromycin derivatives. J Bacteriol 179:6416–6425
Rudolf JD, Yan X, Shen B (2015) Genome neighborhood network reveals insights into enediyne biosynthesis and facilitates prediction and prioritization for discovery. J Ind Microbiol Biotechnol. doi:10.1007/s10295-015-1671-0
Schmitt EK, Hoepfner D, Krastel P (2015) Natural products as probes in pharmaceutical research. J Ind Microbiol Biotechnol. doi:10.1007/s10295-015-1691-9
Shier WT, Rinehart KL, Gottlieb D (1969) Preparation of four new antibiotics from a mutant of Streptomyces fradiae. Proc Natl Acad Sci USA 63:198–204
Shoemaker R (2006) The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer 6:813–823
Skinnider MA, Dejong CA, Rees PN, Johnston CW, Li H, Webster AL, Wyatt MA, Magarvey NA (2015) Genomes to natural products PRediction Informatics for Secondary Metabolomes (PRISM). Nucleic Acids Res 43:9645–9662
Smanski MJ, Schlatter DC, Kinkel LL (2015) Leveraging ecological theory to guide natural product discovery. J Ind Microbiol Biotechnol. doi:10.1007/s10295-015-1683-9
Solenberg PJ, Matsushima P, Stack DR, Wilkie SC, Thompson RC, Baltz RH (1997) Production of hybrid glycopeptide antibiotics in vitro and in Streptomyces toyocaensis. Chem Biol 4:195–202
Sparks TC, Crouse GD, Dripps JE, Anzeveno P, Martynow J, Deamichis CV, Gifford J (2008) Neural network-based QSAR and insecticide discovery: spinetoram. J Comput Aided Mol Des 22:393–4001
Stähelin HF (1996) The history of cyclosporine A (Sandimmun®) revisited: another point of view. Experientia 52:5–13
Stapley EO, Hendlin D, Mata JM, Jackson M, Wallick H, Hernandez S, Mochales S, Currie SA, Miler RN (1969) Phosphonomycin. I. Discovery and in vitro biological characterization. Antimicrob Agents Chemother 9:284–290
Strieker M, Tanović A, Marahiel MA (2010) Nonribosomal peptide synthetases: structure and dynamics. Curr Opin Struct Biol 7:77–84
Strohl WR, Woodruff HB, Monaghan RL et al (2001) The history of natural products research at Merck & Co. SIM News 51:5–19
Summers RG, Donadio S, Staver MJ, Wendt-Pienkowski E, Hutchinson CR, Katz L (1997) Sequencing and mutagenesis of genes from the erythromycin biosynthetic gene cluster from Saccharopolyspora erythraea that are involved in l-mycarose and d-desosamine production. Microbiology 143:3251–3261
Swinney DC, Anthony J (2011) How were new medicines discovered? Nat Rev Drug Discov 10:507–519
Tanaka H, Nishiyama T, Amano S, Beppu T, Kobayashi M, Ueda K (2015) Streptomyces metabolites in divergent microbial interactions. J Ind Microbiol Biotechnol. doi:10.1007/s10295-015-1680-z
Tang L, Fu H, McDaniel R (2000) Formation of functional heterologous complexes using subunits from the pikromycin, erythromycin and oleandomycin synthases. Chem Biol 7:77–84
Tang L, Chung L, Carney JR, Starks CM, Licari P, Katz L (2005) Generation of new epothilones by genetic engineering of a polyketide synthase in Myxococcus xanthus. J Antibiot 58:178–184
Terstappen G, Schlüpen C, Raggiaschi R, Gaviraghi G (2007) Target deconvolution strategies in drug discovery. Nat Rev Drug Discov 6:891–903
Thaker MN, Waglechner N, Wright GD (2014) Antibiotic resistance-mediated isolation of scaffold-specific natural product producers. Nat Protoc 9:1469–1479
Tietz JI, Mitchell DA (2015) Using genomics for natural product structure elucidation. Curr Top Med Chem (Epub ahead of print)
Turner J, Krupinski VM, Fukuda DS, Baltz RH (1985) Process for preparing macrocin derivatives. US patent 4,559,301
Umezawa H (1965) Bleomycin and other antibiotics of high molecular weight. Antimicrob Agents Chemother 5:1079–1085
Vezina C, Kudelski A, Sehgal SN (1975) Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot 28:721–726
Wagman GH, Weinstein MJ (1980) Antibiotic from Micromonospora. Ann Rev Microbiol 34:537–557
Waldron C, Matsushima P, Rosteck PR, Broughton MC, Turner J, Madduri K, Crawford KP, Merlo DJ, Baltz RH (2001) Cloning and analysis of the spinosad biosynthetic gene cluster of Saccharopolyspora spinosa. Chem Biol 8:487–499
Weber T, Blin K, Duddela S et al (2015) antiSMASH 3.0—a comprehensive resource for the genome mining of biosynthetic gene clusters. Nucleic Acids Res 43:w237–w243
Weinstein MJ (2004) Micromonospora antibiotic discovery at Schering/Schering Plough (1961–1973). SIM News 54:56–66
Weissman KJ (2015) The structural biology of biosynthetic megaenzymes. Nat Chem Biol 11:660–670
Weist S, Süssmuth RD (2005) Mutational biosynthesis—a tool for the generation of structural diversity in the biosynthesis of antibiotics. Appl Microbiol Biotechnol 68:141–150
Whicher JR, Dutta S, Hansen DA et al (2014) Structural rearrangements of a polyketide synthase module during its catalytic cycle. Nature 510:560–564
Wright GD (2007) The antibiotic resistome: the nexus of chemical and genetic diversity. Nat Rev Microbiol 5:175–186
Wu C, Choi YH, van Wezel G (2015) Metabolic profiling as a tool for prioritizing antimicrobial compounds. J Ind Microbiol Biotechnol. doi:10.1007/s10295-015-1666-x
Yoon V, Nodwell JR (2014) Activating secondary metabolism with stress and chemicals. J Ind Microbiol Biotechnol 41:415–424
Zhu H, Sandiford SK, van Wezel GP (2014) Triggers and cues that activate antibiotic production by actinomycetes. J Ind Microbiol Biotechnol 41:371–386
Zhu H, Wang W, Liu J, Caijin Q, Qiao J (2015) Immobilization of Streptomyces thermotolerans 11432 on polyurethane foam to improve production of Acetylisovaleryltylosin. J Ind Microbiol Biotechnol 42:105–111
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Special Issue: Natural Product Discovery and Development in the Genomic Era. Dedicated to Professor Satoshi Ōmura for his numerous contributions to the field of natural products.
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Katz, L., Baltz, R.H. Natural product discovery: past, present, and future. J Ind Microbiol Biotechnol 43, 155–176 (2016). https://doi.org/10.1007/s10295-015-1723-5
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DOI: https://doi.org/10.1007/s10295-015-1723-5