Importance of microbial natural products and the need to revitalize their discovery

Journal of Industrial Microbiology and Biotechnology

Volumn 41, Issue 2, 2014, Pages 185-201

  Demain, Arnold L ^a  

^a DREW UNIVERSITY   (United States)

Author keywords

Antibiotics; Anticancer; Drug discovery; Hypocholesterolemics; Immunosuppressants; Microbial natural products

Indexed keywords

ANTI-BACTERIAL AGENTS; ANTINEOPLASTIC AGENTS; BIOLOGICAL PRODUCTS; DRUG DISCOVERY; GENOME, MICROBIAL; IMMUNOSUPPRESSIVE AGENTS; SECONDARY METABOLISM;

EID: 84895074954     PISSN: 13675435     EISSN: 14765535     Source Type: Journal    
DOI: 10.1007/s10295-013-1325-z     Document Type: Review

References (127)

1. Alarcon J, Aguila S, Arancibia-Avila P, Fuentes O, Zamorano-Ponce E, Hernandez M (2003) Production and purification of statins from Pleurotus ostreatus (Basidiomycetes) strains. Z Naturforsch 58:62-64
2. Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, Rothrock J, Lopez M, Joshua H, Harris E, Patchett A, Monaghan R, Currie S, Stapley E, Albers-Schonberg G, Hensens O, Hirshfield J, Hoogsteen K, Liesch J, Springer J (1980) Mevinolin. A highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA 77:3957-3961
3. Alsberg CL, Black OF (1913) Contributions to the study of maize deterioration. Biochemical and toxological investigations of Penicillium puberulum and Penicillium stoloniferum. USDA Bur. Plant Ind., Bull. No. 270, Govt. Printing Office, Washington, DC
4. Amaya T, Hiroi J, Lawrence ID (2002) Tacrolimus and other immunosuppressive macrolides in clinical practice. In: Omura S (ed) Macrolide antibiotics: chemistry, biology and practice, 2nd edn. Academic/Elsevier, San Diego, pp 421-452
5. Amna T, Puri SC, Verma V, Sharma JP, Khajuria RK, Spiteller M, Qasi GN (2006) Bioreactor studies on the endophytic fungus Entrophospora for the production of an anticancer alkaloid camptothecin. Can J Microbiol 52:189-196
6. Asaduzzaman SM, Sonomoto K (2009) Lantibiotics: diverse activities and unique modes of action. J Biosci Bioeng 107:475-487
7. Baltz RH (2007) Antimicrobials from actinomycetes: back to the future. Microbe 2:125-131
8. Baltz RH (2012) Combinatorial biosynthesis of cyclic lipopeptide antibiotics: a model for synthetic biology to accelerate the evolution of secondary metabolic biosynthetic pathways for nonribosomal peptides. ACS Synth Biol (dx.doi.org/ 10.1021/sb3000673)
9. Bender RP, Jablonksy MJ, Shadid M, Romaine I, Dunlap N, Anklin C, Graves DE, Osheroff N (2008) Substituents on etoposide that interact with human topoisomerase IIα in the binary enzyme-drug complex: contributions to etoposide binding and activity. Biochemistry 46:4501-4509
10. Bentley R (2001) Bartolomeo Gosio, 1863-1944; an appreciation. Adv Appl Microbiol 48:229-250
11. Bevan MW, Franssen MCR (2006) Investing in green and white biotech. Nat Biotechnol 24:765-767
12. Birkinshaw JH, Raistrick H, Ross DJ (1952) Studies in the biochemistry of micro-organisms. 86. The molecular constitution of mycophenolic acid, a metabolic product of Penicillium brevi-compactum Dierckx. Part 3. Further observations on the structural formula for mycophenolic acid. Biochem J 50:630-634
13. Bode HB, Bethe B, Hofs R, Zeeck A (2002) Big effects from small changes: possible ways to explore nature's chermical diversity. ChemBioChem 3:619-627
14. Bok JW, Hoffmeister D, Maggio-Hall LA, Murillo R, Glasner JD, Keller NP (2006) Genomic mining for Aspergillus natural products. Chem Biol 13:31-37
15. Brakage AA, Schroekh V (2011) Fungal secondary metabolites - strategies to activate silent genes. Fungal Genet Biol 48:15-22
16. Breinbauer R, Manger M, Scheck M, Waldmann H (2002) Natural product guided compound library development. Curr Med Chem 9:2129-2145
17. Breinbauer R, Vetter JR, Waldmann H (2002) From protein domains to drug candidates - natural products as guiding principles in the design and synthesis of compound libraries. Angew Chem Int Ed 41:2879-2890
18. Bringi V, Kadkade PG (1993) Enhanced production of taxol and taxanes by cell cultures of Taxus species. Patent WO93/17121
19. Bronson JJ, Barrett JF (2001) Quinolone, everninomycin, glycylcycline, carbapenem, lipopeptide and cephem antibiotics in clinical development. Curr Med Chem 8:1775-1793
20. Brown AG, Smale TC, King TJ, Hasenkamp R, Thompson RH (1976) Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium brevicompactum. J Chem Soc Perkins Trans I:1165-1170
21. Bull AT, Ward AC, Goodfellow M (2000) Search and discovery strategies for biotechnology: the paradigm shift. Microbiol Mol Biol Rev 64:573-606
22. Burrill GS (2002) Personalized medicine or blockbusterology. BioPharm 15(4):46-50
23. Busti E, Monciardini P, Cavaletti L, Bamonte R, Lazzarini A, Sosio M, Donadio S (2006) Antibiotic-producing ability by representatives of a newly discovered lineage of actinomycetes. Microbiology 152:675-683
24. Campbell WC (2012) History of avermectin and ivermectin, with notes on the history of other macrocyclic lactone antiparasitic agents. Curr Pharm Biotechnol 13:853-865
25. Cao Y, Langer R (2008) A review of Judah Folkman's remarkable achievements in biomedicine. Proc Natl Acad Sci USA 105:13203-13205
26. Cao K, Graziotto JJ, Blair CD, Mazzulli JR, Erdos MR, Krainc D, Collins FS (2011) Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. Sci Translat Med 3(89):1-11
27. Cardenas ME, Shane Cutler N, Lorenz MC, Di Como CJ, Heitman J (1999) The TOR signaling cascade regulates gene expression in response to nutrients. Genes Devel 13:3271-3279
28. Carle P, Graeber M, Stuetz A (2000) Ascomycins: promising agents for the treatment of inflammatory skin diseases. Expert Opin Investig Drugs 9:69-77
29. Chan KY, Boucher ES, Gandhi PJ, Silva MA (2004) HMG-CoA reductase inhibitors for lowering elevated levels of C-reactive protein. Am J Health-Syst Pharm 61:1676-1681
30. Choi H-K, Kim S-I, Son J-S, Hong S-S, Lee H-S, Chung I-S, Lee H-J (2000) Intermittent maltose feeding enhances paclitaxel production in suspension culture of Taxus chinensis cells. Biotechnol Lett 2:1793-1796
31. Christoffersen RE (2006) Antibiotics. an investment worth making? Nat Biotechnol 24:1512-1514
32. Connors N, Pollard D (2004) Pneumocandin BO production by fermentation of the fungus Glarea lozoyensis: physiological and engineering factors affecting titer and structural analogue formation. In: An Z (ed) Handbook of Industrial Mycology. Marcel Dekker, NY, pp 515-538
33. Cragg GM, Newman DJ (2000) Antineoplastic agents from natural sources: achievements and future directions. Expert Opin Investig Drugs 9:2783-2797
34. Cruz MC, Del Poeta M, Wang P, Wenger R, Zenke G, Quesniaux VFJ, Movva NR, Perfect JR, Cardenas ME, Heitman J (2000) Immunosuppressive and nonimmunosuppressive cyclosporine analogs are toxic to the opportunistic fungal pathogen Cryptococcus neoformans via cyclophillin-dependent inhibition of calcineurin. Antimicrob Ag Chemother 44:143-149
35. Cruz MC, Goldstein AL, Blankenship J, Del Poeta M, Perfect JR, McCusker JH, Bennani YL, Cardenas ME, Heitman J (2001) Rapamycin and less immumosuppressive analogs are toxic to Candida albicans and Cryptococcus neoformans via FKBP12-dependent inhibition of TOR. Antimicrob Ag Chemother 45:3162-3170
36. Dejong JM, LiuY Bollon AP, Long RM, Jennewein S, Williams D, Croteau RB (2006) Genetic engineering of taxol biosynthetic genes in Saccharomyces cerevisiae. Biotechnol Bioeng 93:212-224
37. Demain AL (2002) Prescription for an ailing pharmaceutical industry. Nat Biotechnol 20:331
38. Demain AL (2006) From natural products discovery to commercialization: a success story. J Ind Microbiol Biotechnol 33:486-495
39. Demain AL, Adrio JL (2008) Contributions of microorganisms to industrial biology. Mol Biotechnol 38:41-55
40. Demain AL, Zhang L (2005) Natural products and drug discovery. In: Zhang L, Demain AL (eds) Natural products: drug discovery and therapeutic medicine. Humana Press, Totowa, pp 3-29
41. Deorukhkar A (2007) Back to basics: how natural products can provide the basis for new therapeutics. Expert Opin Investig Drugs 16:1753-1773
42. Dobson S, May T, Berriman M, Del Vecchio C, Fairlamb AH, Chakrabarti D, Bavic S (1999) Characterization of protein Ser/Thr phosphatases of the malaria parasite, Plasmodium falciparum: inhibition of the parasitic calcineurin by cyclophilin-cyclosporin complex. Molec Biochem Parasitol 99:167-181
43. Dunlap WC, Battershill CN, Liptrot CH, Cobb RE, Bourne DG, Jaspars M, Long PF, Newman DJ (2007) Biomedicinals from the phytosymbionts of marine invertebrates: a molecular approach. Methods 42:358-376
44. Dworkin M (2007) Lingering puzzles about myxobacteria. Microbe 2:18-24
45. Eckstein JW, Fung J (2003) A new class of cyclosporin analogues for the treatment of asthma. Expert Opin Investig Drugs 12:647-653
46. Einhorn LH (2002) Curing metastatic testicular cancer. Proc Natl Acad Sci (USA) 99:4592-4595
47. Endo A (2010) A historical perspective on the discovery of statins. Proc Jpn Acad Ser B 86:484-492
48. Endo A, Kuroda M, Tanzawa K (1976) Competitive inhibition of 3-hydroxyglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett 72:323-326
49. Endo A (1980) Monocolin K, a new hypocholesterolemic agent that specifically inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase. J Antibiot 33:334-336
50. Engels EA, Biggar RJ, Hall HI, Cross H, Crutchfield A, Finch JL, Grigg R, Hylton T, Pawlish KS, McNeel TS, Goedert JJ (2008) Cancer risk in people infected with human immunodeficiency virus in the United States. Intl J Cancer 123:187-194
51. Ernst and Young (2000) The Ernst & Young Fifteenth Annual Report on the Biotechnology Industry. Ernst & Young LLP
52. Felnagle EA, Jackson EE, Chan YA, Podevels AM, Berti AD, McMahon MD, Thomas MG (2008) Nonribosomal peptide synthetases involved in the production of medically relevant natural products. Molec Pharmaceut 5:191-211
53. Georgopapadakou NH (2001) Antifungals targeted to cell wall: focus on β-1,3-glucan synthase. Expert Opin Investig Drugs 10:269-280
54. Gerth K, Steinmetz H, Hofle G, Reichenbach H (2000) Studies on biosynthesis of epothilones: the biosynthetic origin of the carbon skeleton. J Antibiot 53:1373-1377
55. Gold BG (2000) Neuroimmunophilin ligands: evaluation of their therapeutic potential for the treatment of neurological disorders. Expert Opin Investig Drugs 9:2331-2342
56. Goodin S (2008) Novel cytotoxic agents: epothilones. Am J Health Syst Pharm 65(10 Suppl 3):S10-S15
57. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nature Med 8:128-135
58. Guilder TAM, Moore BS (2009) Chasing the treasures of the sea - bacterial marine natural products. Curr Opin Microbiol 12:252-260
59. Hardt IH, Steinmetz H, Gerth K, Sasse F, Reichenbach H, Höfle G (2001) New natural epothilones from Sorangium cellulosum, Strains So ce90/B2 and So ce90/D13: isolation, structural elucidation, and SAR studies. J Nat Prods 64:847-856
60. Hopwood D, Malpartida F, Kieser HM, Ikeda H, Duncan J, Fujii I, Rudd BAM, Floss HG, Omura S (1985) Production of hybrid antibiotics by genetic engineering. Nature 314:642-644
61. Hranueli D, Cullum J, Basrak B, Goldstein P, Long PF (2005) Plasticity of the Streptomyces genome-evolution and engineering of new antibiotics. Curr Med Chem 12:1697-1704
62. Hugonnet J-E, Tremblay LW, Boshoff HI, Barry CE 3rd, Blanchard JS (2009) Meropenem-clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis. Science 323:1215-1218
63. Jensen PR, Mincer TJ, Williams PG, Fenical W (2005) Marine actinomycete diversity and natural product discovery. Ant v Leeuwenhoek 87:43-48
64. Kingston DGI, Newman DJ (2002) Mother nature's combinatorial libraries; their influence on the synthesis of drugs. Curr Opin Drug Disc Devel 5:304-316
65. Knowles J, Gromo G (2003) Target selection in drug discovery. Nat Rev 2:63-69
66. Kumaran RS, Muthumary JP, Hur B-K (2008) Taxol from Phyllosticta citricarpa, a leaf spot fungus of the angiosperm Citrus medica. J Biosci Bioeng 106:103-106
67. Lederberg J (2000) Pathways of discovery: infectious history. Science 288:287-293
68. Lee HJ, Lee HJ, Magesh V, Nam D, Lee EO, Ahn KS, Jung MH, Ahn KS, Kim DK, Kim JY, Kim SH (2008) Shikonin, acetylshikonin, and isobutyroylshikonin inhibit VEGF-induced angiogenesis and suppress tumor growth in Lewis lung carcinoma-bearing mice. Yakugaku Zasshi 128:1681-1688
69. Liu X-H, Zhao L-B, She Z-G, Lin YC (2004) Recent progress in bioactive metabolites of marine microorganisms. Chi J Antibiot 29:492-510
70. Lorence A, Nessler CL (2004) Camptothecin, over four decades of surprising findings. Phytochemistry 65:2735-2749
71. Manzoni M, Rollini M (2002) Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs. Appl Microbiol Biotechnol 58:555-564
72. Manzoni M, Bergomi S, Rollini M, Cavazzoni N (1999) Production of statins by filamentous fungi. Biotechnol Lett 21:253-257
73. Martinkova L, Juzlova P, Vesely D (1995) Biological activity of polyketide pigments produced by the fungus Monascus. J Appl Bacteriol 79:609-616
74. McAlpine J (1998) Unnatural natural products by genetic manipulation. In: DM Sapienza, LM Savage (Eds) Natural Products II: New Technologies to Increase Efficiency and Speed. Internat Bus Comm, Southboro, 251-278
75. Nathan C (2004) Antibiotics at the crossroads. Nature 431:899-902
76. Newman DJ, Cragg GM, Snader KM (2003) Natural products as sources of new drugs over the period 1981-2002. J Nat Prods 66:1022-1037
77. Newman DJ, Cragg GM (2005) in Natural Products: Drug Discovery and Therapeutic Medicine, L. Zhang and A.L. Demain, eds., pp. 129-168, Humana Press, Totowa, NJ
78. Newman DJ, Shapiro S (2008) Microbial prescreens for anticancer activity. SIM News 58:132-150
79. Omura S (2008) Ivermectin: 25 years old and still going strong. J Antimicrob Ag 31:91-98
80. Onyewu C, Blankenship JR, Del Poeta M, Heitman J (2003) Ergosterol biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors in Candida albicans, Candida glabrata, and Candida krusei. Antimicrob Ag Chemother 47:956-964
81. Overbye KM, Barrett J (2005) Antibiotics: where did we go wrong? Drug Disc Today 10:45-52
82. Pandey R, Chander R, Sainis KB (2007) Prodigiosins: a novel family of immunosuppressants with anti-cancer activity. Ind J Biochem Biophys 44:295-302
83. Park SR, Han AR, Ban Y-H, Yoo YJ, Kim EJ, Yoon YJ (2010) Genetic engineering of macrolide biosynthesis: past advances, current state and future prospects. Appl Microbiol Biotechnol 85:1227-1239
84. Park SR, Yoo YJ, Ban Y-H, Yoon YJ (2010) Biosynthesis of rapamycin and its regulation: past achievements and recent progress. J Antibiot 63:434-441
85. Patchett AA (2002) Alfred Burger award address in medicinal chemistry. Natural products and design: interrelated approaches in drug discovery. J Med Chem 45:5609-5616
86. Paululat T, Tang Y-Q, Grabley S, Thiericke R (1999) Combinatorial chemistry: the impact of natural products. Chim Oggi 17:52-56
87. Peng Y, Demain AL (1998) Properties of the hydroxylase in Actinomadura sp cells converting compactin to pravastatin. J Ind Microbiol Biotechnol 20:373-375
88. Piel J, Hui D, Wen G, Butzke D, Platzer M, Fusetani N, Matsunaga S (2004) Antitumor polyketide biosynthesis by an uncultivated bacterial symbiont of the marine sponge Theonella swinhoei. Proc Natl Acad Sci USA 101:16222-16227
89. Pinter G, Batta G, Keki S, Mandi A, Komaromi I, Takacs-Novak K, Sztaricskai F, Roth E, Ostorhazi E, Rozgonyi F, Naesens L, Herczegh P (2009) Diazo transfer-click reaction route to new lipophilic teicoplanin and ristocetin aglycon derivatives with high antibacterial and anti-influenza virus activity: an aggregation and receptor binding study. J Med Chem 52:6053-6061
90. Pray L (2002) Strange bedfellows in transplant drug therapy. Scientist 16(7):36
91. Raskin I, Ribnicky DM, Komarnytsky S, Nabojsa I, Poulev A, Borisjuk N, Brinker A, Moreno DA, Ripoll C, Yakoby N, O'Neal JM, Cornwell T, Pastor I, Fridlender B (2002) Plants and human health in the twentieth century. Trends Biotechnol 20:522-531
92. Revill WP, Voda J, Reeves CR, Chung L, Schirmer A, Ashley G, Carney JR, Fardis M, Carreras CW, Zhou Y, Feng L, Tucker E, Robinson D, Gold BG (2002) Genetically engineered analogs of ascomycin for nerve regeneration. J Pharmacol Exp Ther 302:1278-1285
93. Rini B, Kar S, Kirkpatrick P (2007) Temsirolimus. Nature Rev/Drug Discov 6:599-600
94. Robert J, Jarry C (2003) Multidrug resistance reversal agents. J Med Chem 46:4805-4817
95. Rohde J, Heitman J, Cardenas ME (2001) The TOR kinases link nutrient sensing to cell growth. J Biol Chem 276:9583-9586
96. Rokem JS, Lantz AE, Nielsen J (2007) Systems biology of antibiotic production by microorganisms. Nat Prod Rep 24:1262-1287
97. Scheffler RJ, Colmer S, Tynan H, Demain AL, Gullo V (2013) Antimicrobials, drug discovery, and genome mining. Appl Microbiol Biotechnol 97:969-978
98. Schiewe H-J, Zeeck A (1999) Cineromycins: butyrolactones and ansamycins of the secondary metabolite pattern created by a single strain of Streptomyces. J Antibiot 52:635-642
99. Selitrennikoff CP (2001) Antifungal proteins. Appl Environ Microbiol 67:2883-2894
100. Serizawa N, Matsuoka T (1991) A two-component-type cytochrome P-450 monoxygenase system in prokaryotes that catalyzes hydroxylation of ML-236B to pravastatin, a tissue-selective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Biochim Biophys Acta 1084:35-40
101. Smith L, Hillman JD (2008) Therapeutic potential of type A (I) lantibiotics, a group of cationic peptide antibiotics. Curr Opin Microbiol 11:401-408
102. Soetaert W, Vandamme EJ (2010) Industrial biotechnology. Sustainable growth and economic success. Wiley VCH, Weinheim
103. Song J-H (2008) What's new on the antimicrobial horizon? Intl J Antimicrob Ag 32(Suppl 4):S207-S213
104. Stierle A, Strobel G, Stierle D (1993) Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of Pacific yew. Science 260:214-216
105. Strobel GA (2002) Rainforest endophytes and bioactive products. Crit Rev Biotechnol 22:315-333
106. Strobel GA, Hess WM, Ford E, Sidhu RS, Yang X (1996) Taxol from fungal endophytes and the issue of biodiversity. J Indust Microbiol 17:417-423
107. Strohl WR (2004) Antimicrobials. In: Bull AT (ed) Microbial diversity and bioprospecting. ASM Press, Washington, DC, pp 336-355
108. Topliss JG, Clark AM, Ernst E, Hufford CD, Johnston GAR, Rimoldi JM, Weimann BJ (2002) Natural and synthetic substances related to human health. Pure Appl Chem 74:1957-1985
109. Udwary DW, Zeigler L, Asokar RN, Singan V, Lapidas A, Fenical W, Jensen PR, Moore BS (2007) Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinospora tropica. Proc Natl Acad Sci USA 104:10376-10381
110. Vaishnav P, Demain AL (2009) Industrial biotechnology (overview). In: Schaechter M (Ed) Encyclopedia of microbiology, third edition. Elsevier, 335-348
111. Vandamme EJ (2007) Microbial gems: microorganisms without frontiers. SIM-News 57:81-91
112. Veillard NR, Mach F (2002) Statins: the new aspirin? Cell Mol Life Sci 59:1771-1786
113. Vezina C, Kudelski A, Sehgal SN (1975) Rapamycin (AY-22989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot 28:721-726
114. Waldemann H, Breinbauer R (2002) Nature provides the answer. Screening 3(6):46-48
115. Wall ME, Wani MC (1996) Camptothecin and taxol: from discovery to clinic. J Ethnopharmacol 51:239-254
116. Wang JF, Li GL, Lu HY, Zhang ZH, Huang YJ, Su WJ (2000) Taxol from Tubercularia sp. strain TF5, an endophytic fungus of Taxus mairei. FEMS Microbiol Lett 193:249-253
117. Watkins KJ (2002) Fighting the clock. Chem Eng News 80(4):27-34
118. Wilkinson B, Micklefield J (2007) Mining and engineering natural-product biosynthetic pathways. Nature Chem Bio 3:379-386
119. Wong FT, Khosla C (2012) Combinatorial biosynthesis of polyketides - a perspective. Curr Opin Chem Biol 161:117-123
120. Wrigley SK (2004) Pharmacologically active agents of microbial origin. In: Bull AT (ed) Microbial diversity and bioprospecting. ASM Press, Washington, DC, pp 356-374
121. Xie X, Tang Y (2007) Efficient synthesis of simvastatin by use of whole-cell biocatalysis. Appl Environ Microbiol 73:2054-2060
122. Xie X, Wong WW, Tang Y (2007) Improving simvastatin bioconversion in Escherichia coli by deletion of bioH. Metab Eng 9:379-386
123. Xue Q, Ashley G, Hutchinson CR, Santi DV (1999) A multi-plasmid approach to preparing large libraries of polyketides. Proc Natl Acad Sci USA 96:11740-11745
124. Yang SS, Cragg GM, Newman DJ, Bader JP (2001) Natural product-based anti-HIV drug discovery and development facilitated by the NCI development therapeutics program. J Nat Prods 64:265-277
125. Yoneyama H, Katsumata R (2006) Antibiotic resistance in bacteria and its future for novel antibiotic development. Biosci Biotechnol Biochem 70:1060-1075
126. Youssef S, Stueve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo M, Mitchell DJ, Sobel RA, Steinman L, Zamvil SS (2002) The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420:78-84
127. Zazopoulos E, Huang K, Staffa A, Liu W, Bachmann BO, Nonaka K, Ahlert J, Thorson JS, Shen B, Farnet CM (2003) A genomics-guided approach for discovering and expressing cryptic metabolic pathways. Nat Biotechnol 21:187-190