21st century natural product research and drug development and traditional medicines.

Natural products and related structures are essential sources of new pharmaceuticals, because of the immense variety of functionally relevant secondary metabolites of microbial and plant species. Furthermore, the development of powerful analytical tools based upon genomics, proteomics, metabolomics, bioinformatics and other 21st century technologies are greatly expediting identification and characterization of these natural products. Here we discuss the synergistic and reciprocal benefits of linking these 'omics technologies with robust ethnobotanical and ethnomedical studies of traditional medicines, to provide critically needed improved medicines and treatments that are inexpensive, accessible, safe and reliable. However, careless application of modern technologies can challenge traditional knowledge and biodiversity that are the foundation of traditional medicines. To address such challenges while fulfilling the need for improved (and new) medicines, we encourage the development of Regional Centres of 'omics Technologies functionally linked with Regional Centres of Genetic Resources, especially in regions of the world where use of traditional medicines is prevalent and essential for health.

[1]  A. Nunn,et al.  Global tuberculosis drug development pipeline: the need and the reality , 2010, The Lancet.

[2]  T. Wells Natural products as starting points for future anti-malarial therapies: going back to our roots? , 2011, Malaria Journal.

[3]  S. Klamt,et al.  GSMN-TB: a web-based genome-scale network model of Mycobacterium tuberculosis metabolism , 2007, Genome Biology.

[4]  F. Bucar,et al.  Natural product isolation--how to get from biological material to pure compounds. , 2013, Natural product reports.

[5]  John R Yates,et al.  A Comprehensive Survey of the Plasmodium Life Cycle by Genomic, Transcriptomic, and Proteomic Analyses , 2005, Science.

[6]  Jay D Keasling,et al.  Engineering Escherichia coli for production of functionalized terpenoids using plant P450s. , 2007, Nature chemical biology.

[7]  R. Witkamp,et al.  Metabolomics in the context of systems biology: bridging traditional Chinese medicine and molecular pharmacology , 2005, Phytotherapy research : PTR.

[8]  Márcia M. Almeida-de-Macedo,et al.  A global approach to analysis and interpretation of metabolic data for plant natural product discovery. , 2013, Natural product reports.

[9]  Lorenz von Seidlein,et al.  Artemisinin resistance: current status and scenarios for containment , 2010, Nature Reviews Microbiology.

[10]  Leen Rigouts,et al.  Mycobacterium tuberculosis complex genetic diversity: mining the fourth international spoligotyping database (SpolDB4) for classification, population genetics and epidemiology , 2006, BMC Microbiology.

[11]  Changnan Zhao,et al.  Cloning of artemisinin biosynthetic cDNAs and novel ESTs and quantification of low temperature-induced gene overexpression , 2008, Science in China Series C: Life Sciences.

[12]  C. Saslis-Lagoudakis,et al.  The Use of Phylogeny to Interpret Cross-Cultural Patterns in Plant Use and Guide Medicinal Plant Discovery: An Example from Pterocarpus (Leguminosae) , 2011, PloS one.

[13]  Tran Van Thuy,et al.  Ethnobotany/ethnopharmacology and mass bioprospecting: issues on intellectual property and benefit-sharing. , 2005, Journal of ethnopharmacology.

[14]  B. Barrell,et al.  Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence , 1998, Nature.

[15]  D. Kell Systems biology, metabolic modelling and metabolomics in drug discovery and development. , 2006, Drug discovery today.

[16]  Jaques Reifman,et al.  Quantitative Predictions of Binding Free Energy Changes in Drug-Resistant Influenza Neuraminidase , 2012, PLoS Comput. Biol..

[17]  D. Wishart Applications of Metabolomics in Drug Discovery and Development , 2008, Drugs in R&D.

[18]  Yat T Tang,et al.  Virtual screening for lead discovery. , 2011, Methods in molecular biology.

[19]  David J Newman,et al.  Natural products as sources of new drugs over the 30 years from 1981 to 2010. , 2012, Journal of natural products.

[20]  R. Heinzen,et al.  Host-microbe interaction systems biology: lifecycle transcriptomics and comparative genomics. , 2010, Future microbiology.

[21]  Hong Wang,et al.  Isolation and characterization of AaWRKY1, an Artemisia annua transcription factor that regulates the amorpha-4,11-diene synthase gene, a key gene of artemisinin biosynthesis. , 2009, Plant & cell physiology.

[22]  Yuchun Wang,et al.  Artemisinin: current state and perspectives for biotechnological production of an antimalarial drug , 2006, Applied Microbiology and Biotechnology.

[23]  L. Mooney,et al.  Substandard and Falsified Anti-Tuberculosis Drugs: A Preliminary Field Analysis , 2012, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[24]  D. P. Briskin Medicinal plants and phytomedicines. Linking plant biochemistry and physiology to human health. , 2000, Plant physiology.

[25]  Pilho Kim,et al.  PA-824 Kills Nonreplicating Mycobacterium tuberculosis by Intracellular NO Release , 2008, Science.

[26]  P A Cox,et al.  The ethnobotanical approach to drug discovery. , 1994, Scientific American.

[27]  J. Derisi,et al.  The Transcriptome of the Intraerythrocytic Developmental Cycle of Plasmodium falciparum , 2003, PLoS biology.

[28]  P. Newton,et al.  A Major Genome Region Underlying Artemisinin Resistance in Malaria , 2012, Science.

[29]  T. Cook,et al.  Re-positioning the role of traditional, complementary and alternative medicine as essential health knowledge in global health: do they still have a role to play? , 2009, World health & population.

[30]  D. K. Arrell,et al.  Network Systems Biology for Drug Discovery , 2010, Clinical pharmacology and therapeutics.

[31]  Fan Qu,et al.  Review of current and "omics" methods for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines and mushrooms. , 2012, Journal of ethnopharmacology.

[32]  Timothy S. Ham,et al.  Production of the antimalarial drug precursor artemisinic acid in engineered yeast , 2006, Nature.

[33]  C. Barry,et al.  The mechanism of action of PA-824 , 2009, Communicative & integrative biology.

[34]  Janya Saenboonrueng,et al.  New antimycobacterial and antimalarial 8,9-secokaurane diterpenes from Croton kongensis. , 2003, Journal of natural products.

[35]  J. Vederas,et al.  Drug Discovery and Natural Products: End of an Era or an Endless Frontier? , 2009, Science.

[36]  P. Arsenault,et al.  Trichomes + roots + ROS = artemisinin: regulating artemisinin biosynthesis in Artemisia annua L. , 2011, In Vitro Cellular & Developmental Biology - Plant.

[37]  Hinrich W. H. Göhlmann,et al.  A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis , 2005, Science.

[38]  L. Hood,et al.  Systems medicine: the future of medical genomics and healthcare , 2009, Genome Medicine.

[39]  D. Lun,et al.  Systems biology approaches to understanding mycobacterial survival mechanisms. , 2010, Drug discovery today. Disease mechanisms.

[40]  Bonnie Berger,et al.  MetaMerge: scaling up genome-scale metabolic reconstructions with application to Mycobacterium tuberculosis , 2012, Genome Biology.

[41]  Samuel A. Assefa,et al.  New insights into the blood-stage transcriptome of Plasmodium falciparum using RNA-Seq , 2010, Molecular microbiology.

[42]  J. Laughlin Agricultural production of artemisinin--a review. , 1994, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[43]  L. Barat Four malaria success stories: how malaria burden was successfully reduced in Brazil, Eritrea, India, and Vietnam. , 2006, The American journal of tropical medicine and hygiene.

[44]  Denise E Kirschner,et al.  Tuberculosis: global approaches to a global disease. , 2010, Current opinion in biotechnology.

[45]  Chenfei Ma,et al.  Metabolic fingerprinting investigation of Artemisia annua L. in different stages of development by gas chromatography and gas chromatography-mass spectrometry. , 2008, Journal of chromatography. A.

[46]  Matthias Buck,et al.  The Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilization to the Convention on Biological Diversity , 2011 .

[47]  J. Bayona,et al.  Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis , 2010, The Lancet.

[48]  Jonathan E. Allen,et al.  Genome sequence of the human malaria parasite Plasmodium falciparum , 2002, Nature.

[49]  Alexey Bochkarev,et al.  Genome-scale protein expression and structural biology of Plasmodium falciparum and related Apicomplexan organisms. , 2007, Molecular and biochemical parasitology.

[50]  K. Andries,et al.  Randomized Pilot Trial of Eight Weeks of Bedaquiline (TMC207) Treatment for Multidrug-Resistant Tuberculosis: Long-Term Outcome, Tolerability, and Effect on Emergence of Drug Resistance , 2012, Antimicrobial Agents and Chemotherapy.

[51]  K. Hostettmann,et al.  Twenty years of research into medicinal plants: Results and perspectives , 2002, Phytochemistry Reviews.

[52]  M. Heinrich Ethnopharmacy and natural product research—Multidisciplinary opportunities for research in the metabolomic age , 2008 .

[53]  Esther F. Schmid,et al.  Keynote review: Is declining innovation in the pharmaceutical industry a myth? , 2005, Drug discovery today.

[54]  Gilles Clermont,et al.  Bridging the gap between systems biology and medicine , 2009, Genome Medicine.

[55]  Yansheng Zhang,et al.  The Molecular Cloning of Artemisinic Aldehyde Δ11(13) Reductase and Its Role in Glandular Trichome-dependent Biosynthesis of Artemisinin in Artemisia annua* , 2008, Journal of Biological Chemistry.

[56]  Kyle T. Siebenthall,et al.  Genome variation and evolution of the malaria parasite Plasmodium falciparum , 2007, Nature Genetics.

[57]  Yi Mao,et al.  Dynamical Basis for Drug Resistance of HIV-1 Protease , 2011, BMC Structural Biology.

[58]  Drug discovery and developments in developing countries: bottlenecks and way forward. , 2006, Tanzania health research bulletin.

[59]  Shigehiko Kanaya,et al.  Metabolomics of medicinal plants: the importance of multivariate analysis of analytical chemistry data. , 2010, Current computer-aided drug design.

[60]  Eric Arnoult,et al.  The challenge of new drug discovery for tuberculosis , 2011, Nature.

[61]  Manuel Llinás,et al.  Comparative whole genome transcriptome analysis of three Plasmodium falciparum strains , 2006, Nucleic acids research.

[62]  Yi Li,et al.  The Genetic Map of Artemisia annua L. Identifies Loci Affecting Yield of the Antimalarial Drug Artemisinin , 2010, Science.

[63]  E. Ernst,et al.  Bringing medicinal plants into cultivation: opportunities and challenges for biotechnology. , 2005, Trends in biotechnology.

[64]  H. Wagner,et al.  Application of the "-Omic-" technologies in phytomedicine. , 2007, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[65]  Richard Van Noorden Demand for malaria drug soars , 2010, Nature.

[66]  G. McVean,et al.  Genome-wide variation and identification of vaccine targets in the Plasmodium falciparum genome , 2007, Nature Genetics.

[67]  A. Okunade,et al.  Natural antimycobacterial metabolites: current status. , 2004, Phytochemistry.

[68]  James A. Eddy,et al.  Accomplishments in genome‐scale in silico modeling for industrial and medical biotechnology , 2009, Biotechnology journal.

[69]  H. Masum,et al.  Accelerating Health Product Innovation in sub-Saharan Africa , 2007, Innovations: Technology, Governance, Globalization.

[70]  J. Miller The Discovery of Medicines from Plants: A Current Biological Perspective1 , 2011, Economic Botany.

[71]  H. Wagner,et al.  Synergy research: approaching a new generation of phytopharmaceuticals. , 2009, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[72]  John C. Wootton,et al.  Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum , 2002, Nature.

[73]  Eileen Kraemer,et al.  PlasmoDB: a functional genomic database for malaria parasites , 2008, Nucleic Acids Res..

[74]  A. Hamilton,et al.  Medicinal plants, conservation and livelihoods , 2004, Biodiversity & Conservation.

[75]  Craig M. Crews,et al.  Molecular Understanding and Modern Application of Traditional Medicines: Triumphs and Trials , 2007, Cell.

[76]  Peter H Seeberger,et al.  Continuous-flow synthesis of the anti-malaria drug artemisinin. , 2012, Angewandte Chemie.

[77]  P. Cox The ethnobotanical approach to drug discovery: strengths and limitations. , 1994, Ciba Foundation symposium.

[78]  J. Sachs,et al.  The economic and social burden of malaria , 2002, Nature.

[79]  T. Burkot,et al.  Genetic analysis of the human malaria parasite Plasmodium falciparum. , 1987, Science.

[80]  Bo Zhang,et al.  Network target for screening synergistic drug combinations with application to traditional Chinese medicine , 2011, BMC Systems Biology.

[81]  N. White,et al.  Qinghaosu (Artemisinin): The Price of Success , 2008, Science.

[82]  Liang Liu,et al.  Network-based drug discovery by integrating systems biology and computational technologies , 2012, Briefings Bioinform..

[83]  Santwana Kar,et al.  Control of malaria , 1928, Nature Reviews Drug Discovery.

[84]  Pardis C Sabeti,et al.  A genome-wide map of diversity in Plasmodium falciparum , 2007, Nature Genetics.

[85]  J. Keasling,et al.  Microbially derived artemisinin: a biotechnology solution to the global problem of access to affordable antimalarial drugs. , 2007, The American journal of tropical medicine and hygiene.

[86]  J. Keasling,et al.  Engineering a mevalonate pathway in Escherichia coli for production of terpenoids , 2003, Nature Biotechnology.

[87]  M. Garson,et al.  Antitubercular constituents from the hexane fraction of Morinda citrifolia Linn. (Rubiaceae) , 2002, Phytotherapy research : PTR.

[88]  S. Krishna,et al.  Artemisinins target the SERCA of Plasmodium falciparum , 2003, Nature.

[89]  P. Arsenault,et al.  Reproductive Development Modulates Gene Expression and Metabolite Levels with Possible Feedback Inhibition of Artemisinin in Artemisia annua1[C][W][OA] , 2010, Plant Physiology.

[90]  N. Sangwan,et al.  RAPD profile based genetic characterization of chemotypic variants of Artemisia annua L. , 1999, Biochemistry and molecular biology international.

[91]  Bhushan Patwardhan,et al.  Traditional medicine-inspired approaches to drug discovery: can Ayurveda show the way forward? , 2009, Drug discovery today.

[92]  S. Ambudkar,et al.  Discovering natural product modulators to overcome multidrug resistance in cancer chemotherapy. , 2011, Current pharmaceutical biotechnology.

[93]  V. Singh,et al.  Kinetic modeling of tricarboxylic acid cycle and glyoxylate bypass in Mycobacterium tuberculosis, and its application to assessment of drug targets , 2006, Theoretical Biology and Medical Modelling.

[94]  Abdul Jabbar,et al.  Antimicrobial natural products: an update on future antibiotic drug candidates. , 2010, Natural product reports.

[95]  D. Kwiatkowski How malaria has affected the human genome and what human genetics can teach us about malaria. , 2005, American journal of human genetics.

[96]  P. Clemons,et al.  Distinct Biological Network Properties between the Targets of Natural Products and Disease Genes , 2010, Journal of the American Chemical Society.

[97]  N. Farnsworth,et al.  The value of plants used in traditional medicine for drug discovery. , 2001, Environmental health perspectives.

[98]  J. Stark,et al.  Systems biology of persistent infection: tuberculosis as a case study , 2008, Nature Reviews Microbiology.

[99]  Tatiana Nikolskaya,et al.  Early prediction of drug metabolism and toxicity: systems biology approach and modeling. , 2004, Drug discovery today.

[100]  Jonathan Crabtree,et al.  Comparative genomics of the neglected human malaria parasite Plasmodium vivax , 2008, Nature.

[101]  O. Potterat,et al.  Concepts and technologies for tracking bioactive compounds in natural product extracts: generation of libraries, and hyphenation of analytical processes with bioassays. , 2013, Natural product reports.

[102]  S. Meshnick,et al.  Artemisinin: mechanisms of action, resistance and toxicity. , 2002, International journal for parasitology.

[103]  Jon Cohen,et al.  Infectious disease. Approval of novel TB drug celebrated--with restraint. , 2013, Science.

[104]  C. Buell,et al.  Bioinformatics challenges in de novo transcriptome assembly using short read sequences in the absence of a reference genome sequence. , 2013, Natural product reports.

[105]  John W. Erickson,et al.  Structural basis of drug resistance for the V82A mutant of HIV-1 proteinase , 1995, Nature Structural Biology.

[106]  Michael A Fischbach,et al.  Natural products version 2.0: connecting genes to molecules. , 2010, Journal of the American Chemical Society.

[107]  S Brindha,et al.  Informatics resources for tuberculosis--towards drug discovery. , 2012, Tuberculosis.

[108]  D. Guo,et al.  Global characterization of Artemisia annua glandular trichome transcriptome using 454 pyrosequencing , 2009, BMC Genomics.

[109]  Yi Wang,et al.  Discovering active compounds from mixture of natural products by data mining approach , 2008, Medical & Biological Engineering & Computing.

[110]  William F Reynolds,et al.  Using NMR to identify and characterize natural products. , 2013, Natural product reports.

[111]  S. Aljunid,et al.  Development of health biotechnology in developing countries: can private-sector players be the prime movers? , 2012, Biotechnology advances.

[112]  N. Day,et al.  Artemisinin resistance: current status and scenarios for containment , 2010, Nature Reviews Microbiology.

[113]  George M Church,et al.  Tuberculosis Drug Resistance Mutation Database , 2009, PLoS medicine.

[114]  Lie-Fen Shyur,et al.  Metabolomics for phytomedicine research and drug development. , 2008, Current opinion in chemical biology.