Satoshi Ōmura: in pursuit of nature's bounty
2005; Elsevier BV; Volume: 21; Issue: 3 Linguagem: Inglês
10.1016/j.pt.2005.01.005
ISSN1471-5007
Autores Tópico(s)Parasites and Host Interactions
ResumoProfessor Satoshi Ōmura has spent over 40 years searching for bioactive compounds in naturally occurring microorganisms, discovering more than 330 biomedically and commercially significant compounds in the process. The discovery, development and delivery of the drug ivermectin has pioneered the way for subsequent partnerships between the public and private sectors, as well as international collaborations and drug donation programmes. It has involved a variety of ground-breaking steps, providing a curative drug that will help rid Africa and the world of at least one of the most devastating of all human diseases, onchocerciasis. It has also improved the health of pets and livestock around the globe, and encouraged development of a community-based delivery mechanism that could herald a revolution in public health care in Africa. Professor Satoshi Ōmura has spent over 40 years searching for bioactive compounds in naturally occurring microorganisms, discovering more than 330 biomedically and commercially significant compounds in the process. The discovery, development and delivery of the drug ivermectin has pioneered the way for subsequent partnerships between the public and private sectors, as well as international collaborations and drug donation programmes. It has involved a variety of ground-breaking steps, providing a curative drug that will help rid Africa and the world of at least one of the most devastating of all human diseases, onchocerciasis. It has also improved the health of pets and livestock around the globe, and encouraged development of a community-based delivery mechanism that could herald a revolution in public health care in Africa. Professor Satoshi Ōmura is a man of many hobbies and deep beliefs. His hobbies encompass ancient Japanese calligraphic art, painting, golf and cross-country skiing. But his pre-eminent hobby is science, and in particular the science of macrolide antibiotics. His most profound belief is that naturally occurring microorganisms have the propensity to produce a cornucopia of compounds of incalculable value in biomedicine. Almost 50 years of successful, pioneering research pays testimony to his commitment and foresight. The unique characteristics of Japanese tradition and culture have helped influence the contribution that Ōmura and his large, dedicated and extremely talented pool of researchers have made to the global knowledge base. Success has been rooted in the past with a clear vision of the future, and he would be the first to admit that he has been able to see further by, to paraphrase Sir Isaac Newton, 'being able to stand on the shoulders of giants'. Ōmura is president of The Kitasato Institute, one of Japan's leading research facilities. It was founded in 1914 by Shibasaburo Kitasato, isolator of the tetanus bacilli, discoverer of tetanus antibodies and promoter of serotherapy of the disease, whose overriding philosophy was 'results of research should be applied as quickly as possible for the protection of people from contagious diseases'. This philosophy was propagated by subsequent Kitasato Institute alumni: Kiyoshi Shiga (discoverer of the dysentery bacillus, Shigella dysenteriae); Sahachiro Hata who, together with Paul Ehrlich, discovered salvarsan for syphilis; Shinkichi Umeno, inventor of the rabies vaccination system; and Taichi Kitajima, who carried out pioneering work on the immunotherapy of cholera. Following a stellar early career in Japan, Ōmura moved to the USA to work alongside Max Tishler who, after a 32-year spell of remarkable scientific leadership and productivity at the giant Merck pharmaceutical, had accepted an invitation to become Professor of Chemistry at Wesleyan University. In 1987, President Ronald Reagan, upon bestowing the National Medal of Science on Tishler, described him as 'a giant on the chemical scene these past 50 years'. With his body of work, especially the discovery of avermectin, Ōmura deserves to stand alongside these giants of the past. For over 40 years, Ōmura has devoted himself to studies on bioorganic chemistry, with a strong focus on bioactive substances of microbial origin (Figure 1). His work has been guided by five fundamental creeds; the almost unlimited abilities of microorganisms to produce novel compounds; the crucial need to establish 'gold-standard' screening systems; the recognition that screening is not just a routine exercise; the major contribution of basic research; and the need to apportion highest value to maintaining human relationships and partnerships [1Ōmura S. Philosophy of new drug discovery.Microbiol. Rev. 1986; 50: 259-279PubMed Google Scholar]. Microorganisms produce a wide range of bioactive materials, including plant growth factors, vitamins, alkaloids, enzymes and enzyme inhibitors. They can also perform reactions that are difficult or impossible to carry out under laboratory conditions. The key to exploiting microorganisms and harnessing the tremendous potential they offer is the creation of effective screening systems. This is an area where Ōmura and his co-workers have excelled. Their work has led to the creation of innovative new methods for isolation and culturing, and the development of many novel mechanisms for screening natural substances, in particular several of a cellular nature. For example, hymeglusin, a cholesterol biosynthesis inhibitor, and triacsin, an inhibitor of the acyl-CoA synthetase that activates fatty acids, were identified using Vero cells and yeast mutants. In 1972, they devised a new screening method for β-lactamase inhibitors of microbial origin, designed to cope with the manifestation of bacterial resistance to penicillins and cephalosporins [2Hata T. et al.Studies on penicillinase inhibitors produced by microorganisms.J. Antibiot. (Tokyo). 1972; 25: 473-474Crossref PubMed Scopus (19) Google Scholar]. The method allowed other research groups to discover several new β-lactamase inhibitors of low molecular weight, such as clavulanic acid, olivanic acid and thienamycin. The application of new screening systems for inhibitors of cell wall synthesis led to the discovery of azureomycins A and B, as well as AM-5289 [3Ōmura S. et al.Studies on bacterial cell wall inhibitors. VI. Screening method for the specific inhibitors of peptidogylcan synthesis.J. Antibiot. (Tokyo). 1979; 32: 978-984Crossref PubMed Scopus (22) Google Scholar]. From culture broths showing activity against mycoplasma, three new antibiotics were identified: nanaomycins (effective against dermatomycosis in cattle), frenolicin B (an anticoccidium substance) and cervinomycins (active against anaerobic bacteria). Some herbicides inhibit glutamine synthesis in plant tissue, leading to a fatal build up of NH4+ and to exhaustion of glutamine and other amino acids, so a screening system was created to find substances that prevented growth in Bacillus subtilis in minimal medium but not in the presence of glutamine. As a result, phosalacine (which has broad herbicidal activity against both mono- and dicotyledons) was discovered from a new organism, Kitasatospora phosalacinea [4Takahashi Y. et al.Two new species of the genus Kitasatosporia, Kitasatosporia phosalacinea sp. nov. and Kitasatosporia griseola sp. nov.J. Genet. Appl. Microbiol. 1984; 30: 377-387Crossref Scopus (24) Google Scholar]. Over time, a broad spectrum of novel screening systems have been established, leading to the discovery of a range of new compounds. Prumycin, produced by Streptomyces sp. strain F-1028, was found during screening for chemicals active against plant pathogenic fungi, and downstream research found it to be highly effective against mammary adenocarcinoma in mice [5Ōmura S. et al.Structure of prumycin.J. Chem. Soc. (Perkin). 1974; 0: 1627-1631Crossref PubMed Google Scholar]. Among antibiotics inhibiting protein biosynthesis in eukaryotes, prumycin has a unique mode of action. During screening for antiviral compounds, virustomycin was discovered in Streptomyces sp. strain AM-2604. In addition to its antiviral properties, virustomycin also shows antitrichomonal activity [6Ōmura S. et al.The structure of virustomycin A.J. Antibiot. (Tokyo). 1983; 36: 1783-1786Crossref PubMed Scopus (39) Google Scholar]. Irumamycin is an antibiotic that possesses strong activity against several plant pathogenic fungi [7Ōmura S. et al.Structure of a new antifungal antibiotic, irumamycin.J. Org. Chem. 1982; 47: 5413-5415Crossref Scopus (26) Google Scholar], whereas hitachimycin was discovered via two different screening systems, being isolated from Streptomyces sp. strain KG-2245 as an anticancer compound [8Umezawa I. et al.A new antibiotic, stubomycin.J. Antibiot. (Tokyo). 1981; 34: 259-265Crossref PubMed Scopus (30) Google Scholar] and from strain KM-4297 as an antiprotozoal agent [9Ping X. Streptomyces scabrisporus sp. nov.Int. J. Syst. Evol. Microbiol. 2004; 54: 577-581Crossref PubMed Scopus (20) Google Scholar]. In total, more than 330 novel bioactive compounds have been discovered at the Kitasato Institute under Ōmura's research programme. Of the compounds he either discovered or developed (Box 1) , nanaomycin, staurosporine, vineomycin, herbimycin, avermectin, rokitamycin, setamycin, triacsin, atpenin, tilmicosin and lactacystin, as well as others, have become commonly used globally as medicines, veterinary drugs, agrochemicals and biological reagents. Some have simply stimulated others to conduct further research in a variety of fields. During 1994–1998, for example, over 2500 papers citing staurosporine were published.Microbial metabolites discovered by Ōmura and co-workers that have been used as medicines and/or biological reagentsaMedicinesAnthelmintic (animals and humans): avermectin (ivermectin) (Figure Ia)Antimicrobial (humans): leucomycin A3, rokitamycin (Figure Ib)Antimicrobial (animals): nanaomycin A, tilimicosin (Figure Ic)Antimycoplasmal (animals): frenolicin B (Figure Id)Gastrointestinal motor-stimulating activity (humans): motilide (EM574; under development) (Figure Ie)aSource: Kitasato Institute. Anthelmintic (animals and humans): avermectin (ivermectin) (Figure Ia) Antimicrobial (humans): leucomycin A3, rokitamycin (Figure Ib) Antimicrobial (animals): nanaomycin A, tilimicosin (Figure Ic) Antimycoplasmal (animals): frenolicin B (Figure Id) Gastrointestinal motor-stimulating activity (humans): motilide (EM574; under development) (Figure Ie) aSource: Kitasato Institute. Taking things a step further in the search for novel antibiotics, Ōmura carried out work to investigate the antibiotic cerulenin following its discovery in 1967. The compound is an inhibitor of β-ketoacyl-CoA synthetase, one of a series of fatty acid biosynthetic enzymes. He discovered that cerulenin inhibits polyketide antibiotic biosynthesis, implying that biosynthesis of fatty acids and polyketides is somewhat identical. On the basis of this knowledge, an unnatural chimeramycin (a hybrid antibiotic with a novel skeleton) was produced by adding a different but related polyketide skeleton into a cerulenin-containing medium to inhibit the biosynthesis of the original polyketide skeletons. By expanding on this idea, he and David Hopwood of the John Innes Institute (Norwich, UK) created mederrhodins A and B, the first hybrid antibiotics created by genetic engineering [10Hopwood D.A. et al.Production of 'hybrid' antibiotics by genetic engineering.Nature. 1985; 314: 642-644Crossref PubMed Scopus (275) Google Scholar]. Other research groups have now produced several more. From his formative initial research steps on leucomycin, Ōmura's world-leading research on macrolide antibiotics has led to the isolation and structural analysis of widely used compounds such as leucomycin A3 (josamycin), spiramycin and tylosin. His observations that the gastrointestinal motor-stimulating side-effect of erythromycin was distinct from its antimicrobial activity led him to develop a derivative that lost the latter yet increased the former by up to 3000-fold, offering the potential to use the compound for promoting intestinal contraction in the treatment of alimentary disorders [1Ōmura S. Philosophy of new drug discovery.Microbiol. Rev. 1986; 50: 259-279PubMed Google Scholar]. It is through work on avermectin that Ōmura has made the greatest impact – and more than honored the memory and philosophy of his predecessors. In 1973, he originated a proposal for a programme of research aimed at discovering drugs for human and animal use derived from microbial metabolites. He entered into a partnership with the then Merck, Sharpe and Dohme company, a partnership that would not only flourish but would also have a massive impact in biomedical terms around the world: it has fostered numerous other ground-breaking international partnerships, has resulted in the protection of millions of pets and livestock worldwide, and has improved the lives of hundreds of millions of the world's poorest and most needy people. Within the international collaborative partnership initiated and nurtured by Ōmura, members of the Kitasato Institute team were responsible for isolating microorganisms, identifying active compounds and carrying out in vitro evaluations. Scientists at Merck's commercial laboratories in the USA handled the in vivo work and the development of promising compounds. In only the second year of the collaboration, the Japanese team isolated an organism (a species of actinomycete, strain MA-4680, later named Streptomyces avermitilis) from soil in Shizuoka prefecture. (In 2002, Ōmura's research group put forward morphological, physiological, cellular, biochemical and phylogenetic evidence to reclassify the original microorganism and to rename it Streptomyces avermectinius [11Takahashi Y. et al.Streptomyces avermectinius sp. nov., an avermectin-producing strain.Int. J. Syst. Evol. Microbiol. 2002; 52: 2163-2168Crossref PubMed Scopus (56) Google Scholar]; Figure 2.) It produced a very active class of compounds named the avermectins. In 1975, Merck researchers screened the sample, along with 53 others supplied by Ōmura's team, and found it exhibited excellent antiparasitic activity in mice infected with the nematode worm Nematospiroides dubius. An interdisciplinary team headed by William Campbell investigated the many active components, among which avermectins B1a and B1b were found to possess the highest activity. In 1979, the first paper on avermectins was published [12Burg R.W. et al.Avermectins, new family of potent anthelmintic agents: producing organisms and fermentation.Antimicrob. Agents Chemother. 1979; 15: 361-367Crossref PubMed Scopus (762) Google Scholar]. It described the chemicals as a series of macrocyclic lactone derivatives that lacked antibacterial and antifungal activity but that exhibited extraordinarily potent anthelmintic properties. Up until that time, only a handful of the several thousand microbial fermentation products discovered exhibited any anthelmintic properties. Other papers in the same year described the isolation and chromatographic properties [13Miller T.W. Avermectins, new family of potent anthelmintic agents: isolation and chromatographic properties.Antimicrob. Agents Chemother. 1979; 15: 368-371Crossref PubMed Scopus (149) Google Scholar] and detailed the anthelmintic activity [14Egerton J.R. et al.Avermectins, new family of potent anthelmintic agents: efficacy of the B1A component.Antimicrob. Agents Chemother. 1979; 15: 372-378Crossref PubMed Scopus (277) Google Scholar]. The two most active avermectins were chemically reduced to dihydro derivatives that showed very low mammalian toxicity; a mixture of the derivatives was named ivermectin which, following highly successful testing in mice, cats, dogs and cattle, entered into mass production. Ivermectin was found to target glutamate-gated chloride channels of parasites and insects [15Ōmura S. Mode of action of avermectin.in: Ōmura S. Macrolide Antibiotics – Chemistry, Biology, and Practice. 2nd edn. Academic Press, 2002: 571-576Google Scholar] and soon proved to be the most highly effective, broad-spectrum antiparasitic drug ever introduced, effective against parasites in a wide range of animals. Merck researchers identified particularly remarkable efficiency against endo- and ecto-parasites in horses, cattle, pigs and sheep. It also proved to be extremely efficacious in treating larval heartworms, but not adult worms, and to treat mange and other conditions in dogs. Ever since its introduction onto the veterinary market in 1981, ivermectin has been a bestseller, becoming the leading drug in 1983 and maintaining that position ever since, with annual sales of around US$1 billion. It is used to control insect and mite pests in greenhouses. In capsule formulations, it is injected into trees for control of leafminers and mites. It is commonly used for the treatment of external and internal parasites of pets and livestock, including scabies, and is formulated into several baits for control of cockroaches and ants. By 1986, it had been registered for use in 46 countries and was being used worldwide to treat ∼320 million cattle, 151 million sheep, 21 million horses and 5.7 million pigs [16Anon Twelfth Programme Report. Tropical Disease Research: Progress 1975–94, Highlights 1993–94. WHO/TDR, 1995Google Scholar]. Virtually every horse in the USA was receiving the drug; consequently, the horse nematode Onchocerca cervicalis quickly became almost impossible to find. In the mid-1970s, onchocercasis (or river blindness) remained a major global health problem for which there was virtually no effective treatment. The disease is caused by the parasitic worm Onchocerca volvulus, which lives in the human body for up to 14 years. Each adult female worm produces millions of microscopic larvae (microfilariae) that migrate throughout the body, causing a variety of symptoms. The bite of infected blackflies (Simulium spp) carries immature larval forms of the worms from human to human. Adult worms lodge in nodules under the skin, releasing large numbers of microfilariae into surrounding tissues, which then migrate through the body and, after dying, cause conditions including: serious visual impairment and blindness; skin rashes and lesions; intense itching and depigmentation of the skin; lymphadenitis, resulting in hanging groins and elephantiasis of the genitals; and general debilitation. The disease is found in 35 countries, 28 in tropical Africa, where 99% of infected people live. Isolated foci also occur in Latin America (six countries) and Yemen. Some 18 million people are infected and the disease is responsible for the loss of 1 million disability adjusted life years (DALYs) annually. Campbell's early tests in horses had proved that ivermectin killed O. cervicalis worms, which are closely related to O. volvulus worms and, with the encouragement of P. Roy Vagelos, then president of Merck's research laboratories and later chairman and CEO of the company, work began to investigate the possible use of ivermectin in public health. Merck contacted the World Health Organization (WHO) and joined forces with the Special Programme for Research and Training in Tropical Diseases (TDR), based at WHO headquarters in Geneva, to begin an extensive collaborative research programme in humans. This proved to be a forerunner of the so-called PPPs (Public–Private Partnerships) now being regularly established to deal with the production and distribution of 'public goods', these being essential items for which there may be no likelihood of commercial return. In 1981, clinical trials of ivermectin began in Senegal. Over the next four years, Merck's Mohammed Aziz worked with WHO, the Onchocerciasis Control Programme (OCP) in West Africa and TDR to carry out large-scale field trials involving hundreds of thousands of individuals in Ghana, Guatemala, Cote d'Ivoire, Liberia, Mali, Senegal and Togo. Results showed that a single annual dose of 200 μ/kg−1 of the drug reduced the density of microfilarial worms in the skin to zero after one month, and maintained this level for up to 12 months. In fact, the drug is so safe that up to 800 μ/kg−1 can be tolerated. Although the drug did not kill adult worms, which could continue to produce infective immature forms, it created a dramatic reduction in the number of immature worms, but without producing the same level of Mazzotti reaction (severe itching and eye damage thought to be related to accumulations of dead or dying microfilariae) caused by other available drugs [17Aziz M.A. et al.Efficacy and tolerance of ivermectin in human onchocerciasis.Lancet. 1982; 2: 171-173Abstract PubMed Scopus (190) Google Scholar, 18Aziz M.A. et al.Ivermectin in onchocerciasis.Lancet. 1982; 2: 1456-1457Abstract PubMed Scopus (39) Google Scholar, 19Campbell W.C. et al.Ivermectin: a potent new antiparasitic agent.Science. 1983; 221: 823-828Crossref PubMed Scopus (657) Google Scholar]. Ivermectin has the added benefit of allowing the body to repair minor eye lesions. Taking the drug for the 14-year lifespan of the adult worms would effectively prevent a patient from ever developing the disease that had blighted the African continent and acted as a brake on development for centuries. Following these efforts by a truly international partnership, the human formulation of ivermectin was registered for use by French regulators in 1987. Leading up to this event, discussions were under way both inside and outside Merck to try and establish an acceptable price for the drug, bearing in mind that the primary market was communities with precious little money for day-to-day living, let alone funds to purchase drugs. Fortunately, the prevailing credo of the founder of the company matched that of Ōmura and his team, who agreed to forego their share of income from the product destined for human use. George W. Merck had professed 'Medicine is for the people. It is not for profits'. He had helped set the company's core values with the statement 'how can we bring the best of medicine to each and every person? We cannot rest until the way has been found with our help to bring our finest achievements to everyone'. Implementing those wishes, in the presence of political and public health leaders from around the world, Vagelos announced in 1987 the first-ever mass drug donation from a commercial company. He pronounced that ivermectin, produced under the brand name Mectizan (Figure 3), would be provided free of charge for the treatment of river blindness for 'as long as it is needed'. The Merck company have been true to their word ever since, and have regularly renewed this commitment. Since that announcement, the advent of the drug has transformed the treatment of onchocerciasis to the point where elimination of the disease has become a possibility. It quickly became clear that one of the problems facing those involved in programmes to distribute Mectizan tablets is that of the environment and terrain in which they have to operate. Roads are often impossible to pass – if there are any in the first place. Originally, health workers delivering tablets to communities were frustrated because people were not there when they arrived and they had to wait 2–3 days to check for possible side-effects of the drugs. This was placing intolerable strains on health systems already stretched to breaking point. Fortunately, a host of non-governmental organizations realized the potential and mobilized themselves at national, regional and global levels to take action to help distribute tablets. In 1987, TDR began funding formative work on the concept of 'community-based treatment' using ivermectin. The theory was that the drug was so safe and easy to use that affected communities should be able to undertake their own drug distribution and treatment. The concept proved to be remarkably successful, to the point that, in 1989, WHO announced that ivermectin could henceforth be distributed with minimal supervision. TDR further refined systems to develop Community-Directed Treatment with Ivermectin (CDTI), which became the primary basis of operation of the African Programme for Onchocerciasis Control (APOC). Established in 1995, the aim of APOC is to create, by 2007, sustainable community-directed distribution systems using ivermectin, which will ultimately cover 59 million people in African countries, where the disease remains a serious public health problem and where 15 million people are infected. The ultimate goal is to eliminate the disease in the 17 African nations in which it persists, following the successful control of the disease in the 11 nations of the OCP. Community-directed treatment is not only producing excellent results in the fight against onchocerciasis, it is heralding a potential breakthrough in African public health. Affected villages collect ivermectin tablets, deliver them to everyone eligible and report back to health authorities (and meet all the costs involved themselves – the drug being provided free). Now, researchers are attempting to plug antimalarial, reproductive health, and other medical and health products and mechanisms in an integrated fashion into this user- and health-system-friendly delivery mechanism [20Homeida M. et al.APOC's strategy of community-directed treatment with ivermectin (CTDI) and its potential for providing additional health services to the poorest populations.Ann. Trop. Med. Parasitol. 2002; 96: S93-104Crossref PubMed Scopus (86) Google Scholar]. In 2003, around 56 million people were taking ivermectin once annually to free their lives of the threat of blindness, misery and economic losses caused by onchocerciasis (unpublished data *Anon (2004) Mectizan Donation Program Status Report. Mectizan Program Notes. Newsletter of the Mectizan Donation Programme. Issue 33, Merck (http://www.mectizan.org/mpn33/mpnhtml336.htm).). In the next steps in a remarkable story, the combination of ivermectin and albendazole or ivermectin and diethylcarbamazine have been adopted as the main means of mass treatment in the Global Alliance to Eliminate Lymphatic Filariasis (GAELF). Lymphatic filariasis is one of the most prevalent tropical diseases, with an estimated 120 million people being infected. The disease is reported to be responsible for 5 million DALYs lost annually, ranking it third among tropical diseases in terms of DALYs, after malaria and tuberculosis. The disease remains a major impediment to socioeconomic development (India is estimated to lose US$1 billion annually as a result of it) and it is responsible for immense psychosocial suffering among those affected. Bringing the story almost full circle, ivermectin was registered in 2003 for the treatment of strongyloidiasis, a disease that is prevalent in south-east Asia and, indeed, in the Japanese island of Okinawa. The Japanese are now benefiting directly from the downstream fruits of Ōmura's discovery. Along the way, of course, other benefits have accrued. Royalties from the sale of ivermectin for animal health have helped fund research and development work at the Kitasato Institute and have helped meet the construction costs of a first-class, 440-bed hospital on the grounds of the institute. The hospital also boasts a collection of 1500 paintings, chosen by Ōmura and his late wife, allowing him to indulge in another of his hobbies while creating a bright and friendly environment in which patients can recuperate. Ōmura has also ensured that the benefits of ivermectin are widely distributed, playing a significant role in allowing the drug to be donated free by foregoing any royalties from the use of Mectizan in human health interventions. In further work on avermectin, Ōmura's team has carried out biosynthetic studies employing gene cloning and analysis of nucleotide sequences and their functions. Analysis of the entire S. avermitilis genome was achieved in 2003 [21Ōmura S. et al.Genome sequence of an industrial microorganism Streptomyces avermitilis: deducing the ability of producing secondary metabolites.Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 12215-12220Crossref PubMed Scopus (693) Google Scholar, 22Ikeda H. et al.Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis.Nat. Biotechnol. 2003; 21: 526-531Crossref PubMed Scopus (1016) Google Scholar], representing mapping of the biggest bacterial genome reported to date. The result will provide opportunities to elucidate the productivity of microbial secondary metabolites at the genetic level. The longest journey begins with the first step, but the destination is not yet reached. It is unlikely that ivermectin treatment alone can provide a complete and sustainable solution to onchocerciasis; indeed, a conference in 2003 concluded that eradication is not possible with the current tools [23Dadzie Y. et al.Final report of the Conference on the eradicability of Onchocerciasis.Filaria. J. 2003; 2: 2Crossref PubMed Scopus (149) Google Scholar]. Modeling has identified that using drugs that kill or sterilize adult worms would be necessary to achieve eradication [24Alley W.S. et al.Macrofilaricides and onchocerciasis control, mathematical modelling of the prospects for elimination.BMC Public Health. 2001; 1: 12Crossref PubMed Scopus (37) Google Scholar], so it is not surprising to find that Ōmura has a very promising potential macrofilaricide, nafuredin, among his armamentarium of compounds awaiting development. Like any good cross-country skier, Ōmura is staying in the tracks; now, however, he has several sets of tracks to choose from. In what could prove yet another important discovery, his team have isolated two compounds from a common soil fungus that prevent the accumulation of lipids – the initial stages of atherosclerosis. In macrophages, the compounds, known as beauveriolides, inhibit lipid droplet formation, cholesterol ester synthesis and the activity of acyl-CoA:cholesterol acyltransferase (ACAT). In mice, the beauveriolides reduced atherosclerotic formation to half that observed in controls. Significantly, the compounds did not have the unwanted side-effects of diarrhea and adrenal tissue damage shown by many other ACAT inhibitors previously tested for the treatment of atherosclerosis [25Namatame I. et al.Antiatherogenic activity of fungal beauveriolides, inhibitors of lipid droplet accumulation in macrophages.Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 737-742Crossref PubMed Scopus (83) Google Scholar]. Interleukin (IL)-6 is a multifunctional cytokine involved in regulation of differentiation, antibody production and growth of tumor cells. When produced to excess, it plays a major role in the pathogenesis of multiple myeloma and post-menopausal osteoporosis. While screening for IL-6 inhibitors, madindoline A (MDL-A) and madindoline B were found; both have furoindoline structure with diketocyclopentene bound to the methyl group. MDL-A binds to gp130 in a dose-dependent manner, and shows no cytotoxic activity, marking it as a good candidate for treatment of hormone-dependent post-menopausal osteosporosis with a novel mode of action [26Hayashi M. et al.Suppression of bone resorption by madindoline A, a novel non-peptide antagonist to gp130.Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 14728-14733Crossref PubMed Scopus (82) Google Scholar]. Another pioneering venture has been established at the Kitasato Institute, making full use of the Institute's screening infrastructure and systems to help discover more public goods. An altruistic PPP, the JPMW Alliance (involving the Japanese pharmaceutical industry, the Ministry of Health, Labour and Welfare, and TDR) was established in 1999. Ōmura's team are evaluating compounds donated from the chemical libraries of 14 leading Japanese pharmaceutical companies, as well as the natural products arising from research at the Institute itself, for their potential to be developed into novel antimalarial drugs. Compounds and natural product extracts are analyzed first for activity against malaria parasites and then, if active, in a rodent malaria model. So far, some 29 000 samples have been screened and, of the 400 compounds showing preliminary activity, more than 170 have progressed to the rodent model, with 15 or so showing strong potential. One natural product, borrelidin, is a very promising compound. It exhibits novel antimalarial activity and appears more potent that any existing drugs, including the artemisinin derivatives. Following the success of the JPMW project, the Institute is now extending its work, searching for compounds that have activity against other so-called 'neglected diseases' such as African trypanosomiasis and leishmaniasis. Research at the Kitasato Institute is seeing progress in the search for anti-HIV, anti-tuberculosis and antimalaria compounds, as well as in the field of what Ōmura has coined 'anti-infective' agents. He continues to envisage nothing but future successes. His experiences have shown that one in three of soil isolates tested have produced antimicrobial substances. More than 20 000 antibiotics have been produced thus far and that number should rise significantly, offering hope to ease the current dearth of effective products. Recently, high performance liquid chromatography for extraction and purification, and nuclear magnetic resonance spectrometry for elucidation of chemical structure, along with high-throughput screening, combinatorial chemistry and other new technologies, have revolutionized and expedited the isolation and analysis of minute quantities of active substances. He believes that it will be possible to identify and produce many new antibiotics, as well as a wealth of other bioactive compounds – but only if novel screening systems are devised and operated, and compounds developed and marketed, by committed and devoted partnerships that enshrine the philosophy of science for the common good.
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