Saturday, September 20, 2014

Mining drugs from microbes all over the world

Bacteria and fungi do a lot for us. They help us make foods (yogurt, bread), beverages (beer, wine), and condiments (vinegar, kimchi), and can themselves be eaten (nutritional yeast). More generally, microbes have a critical role in ensuring the soil we use to grow useful plants is laden with nutrients. In the last century, microbes have also provided us with a rich collection of novel chemicals from which we've developed many useful drugs.

As a result of their propensity toward high density living, bacteria and fungi frequently find themselves in situations where it is both possible and useful to interact with one another. Microbes accomplish these interactions by making and releasing specialized chemicals into their surrounding environment, which then act on their neighbours. The utility of these chemicals, combined with a couple billion years worth of evolution and diversification, has rendered microbes a venerable powerhouse for the production of chemicals capable of influencing biological activities.

We've managed to track down and isolate enough of the more antagonistic chemicals to build ourselves a handy armament of drugs to fight bacterial and fungal infections, essentially using the microbial world against itself (unfortunately, this is shaping up to spectacularly backfire). Further, microbe-produced chemicals have been developed into drugs used to suppress our immune system (thus permitting organ/bone marrow transplants and the treatment of autoimmune diseases such as rheumatoid arthritis), kill parasites or cancer cells, and even lower blood glucose levels (which is rather helpful if you have diabetes).

I was interested in compiling a list of all known locations from which a microbe producing a drug that eventually made it through clinical trials and onto the market was isolated. Based on the 47 complete sets of location-microbe-drug I've managed to track down to date (unfortunately, I was unable to uncover the isolation location for at least a dozen other drug-producing microbes), here are a couple of findings:

Type of microbe %
Filamentous bacterium - genus Streptomyces 55.3
Filamentous bacterium - other genus 19.1
Filamentous fungi (mould) 14.9
Non-filamentous bacterium 10.6

Most of the microbes responsible for successful drugs were affiliated with the genus Streptomyces, a large group of filamentous (thread-like) bacteria historically classified as fungi (streptomyces = bent/twisted fungus). Members of this genus are well known as prodigious chemical producers.

Threads of Streptomyces venezuelae (magnified 975x)

Continent %
Asia 31.9
North America 31.9
Europe 17.0
South America 10.6
Africa 6.4
Oceania 2.1

With the exception of Antarctica, microbes from every continent have been successfully exploited for their production of pharmacologically useful chemicals. If I was a bioprospector, I'd be taking a gander at Africa and Oceania.

Country %
United States 29.8
Japan 21.3
Italy 6.4
France 4.3
India 4.3
Venezuela 4.3
(Other countries) 29.8

Looking at specific countries, most of the microbes from which drugs have been developed initially resided in either the United States (particularly New Jersey, center of operations for noted soil microbiologist and drug discoverer extraordinaire Selman Waksman) or Japan. I'm guessing these numbers are largely indicative of where drug manufacturers and their soil-collecting employees resided, as opposed to where drug-producing microbes tend to be concentrated.

Interestingly, if you include Japan, about a third of all successful drug-producing microbes were found on (or in shallow waters near) islands. Other drug-making microbe inhabiting islands of note include Borneo, Easter Island, Mauritius, Panay (the Philippines), and Sardinia.

Isolation source %
Soil 85.1
Rotting plant matter 6.4
Water 4.3
Another organism 4.3

Most soils are densely packed with diverse communities of bacteria and fungi, making them an easy target for drug discovery. Drug-producing microbes have typically been recovered from soil samples collected by or for drug company scientists. Many microbes were found simply by digging about on the grounds of the university or drug company where a scientist worked. Slightly more exciting examples include:
  • a chemist in Indianapolis who asked a couple of missionaries hanging out in Borneo to send him soil samples, one of which happened to contain a bacterium that made vancomycin, an antibacterial drug
  • a drug company scientist on vacation in Norway who scooped up a bit of earth from the side of the road after stopping to admire the scenery, which happened to contain a fungus that made ciclosporin, a revolutionary immunosuppressive drug
Notably, there's been a huge emphasis on terrestrial exploration, even though most of the Earth is covered by water.

The other organisms from which drug-producing microbes were isolated were a tropical sea slug and a girl with a badly broken (and infected) leg.

Drug type %
Antibacterial 53.2
Anticancer 17.0
Antifungal 10.6
Immunosuppressive 10.6
Antiparasitic 8.5
Antidiabetes 2.1
β-lactamase inhibitor 2.1

Note: These don't add up to 100% since some of the drugs have more than one use.

Lots of antibacterial drugs have been developed from microbes, likely reflecting the focus of scientists (and drug companies) in the post-penicillin research boom of the '50s and '60s. While American microbes have largely been exploited for their antibacterial chemical products, Japan has been a major source of microbe-derived anticancer drugs.

Google has a nifty map making tool, so I made a map including all of the drug-producing microbe discovery locations more specific than 'somewhere in New Jersey':



For the more intrepid reader, here's a detailed list of the drug-producing microbe discovery locations I've uncovered so far:


North America

- A filamentous fungus called Penicillium chrysogenum (chrysogenum = gold producing, referring to its production of a yellow pigment) that produces the antibacterial drug penicillin progenitor of the penicillin class of antibacterial drugs (e.g. amoxicillin (Amoxil)) was isolated from a mouldy cantaloupe found in a grocery market in Peoria, Illinois, United States by a researcher named Mary Hunt who was looking for a better penicillin-producing Penicillium strain than the one originally discovered by Fleming in 1928 (better, in this case, meant being able to produce lots of penicillin when submerged in tanks, which was necessary to scale up production of the drug) (Raper, 1946; Hoeprich, 1968)

Penicillin at the Nobel Museum in Stockholm (Source)

- A filamentous bacterium called Streptomyces rimosus (rimosus = full of cracks or fissures, referring to the cracked appearance of its colonies when grown on certain solid growth media) that produces the bright yellow antibacterial drug oxytetracycline (trade name Terramycin) was isolated from soil collected at a Pfizer (the company that developed the drug) manufacturing site in Terre Haute, Indiana, United States (Finlay et al., 1950; Nelson and Levy, 2011)

- A filamentous bacterium called Streptomyces achromogenes (achromogenes = not producing colour, referring to its lack of distinctive pigment production) that produces the anticancer drug streptozotocin (trade name Zanosar) was isolated from uncultivated sandy grassland soil collected in Blue Rapids, Kansas, United States (Bergy et al., 1962) (http://www.bacterio.net/streptomycesa.html)

- A filamentous fungus called Aspergillus fumigatus that produces the antiparasitic drug fumagillin (trade name Flisint) was isolated from soil collected somewhere in Kalamazoo County, Michigan, United States (McCowen et al., 1951; Hanson and Eble, 1953; Desoubeaux et al., 2013)

- A filamentous bacterium called Streptomyces aureofaciens that produces the antibacterial drug chlortetracycline (trade name Aureomycin) (aureofaciens = gold producing, referring to its production of a golden yellow pigment) (the drug is also golden yellow in colour) was isolated from soil collected from a plot of dormant timothy (a grass native to Europe) on Sanborn Field, an agricultural experiment field located on the University of Missouri campus outside Columbia, Missouri, United States (Duggar, 1948; Jukes, 1985; Groth et al., 2003; Nelson and Levy, 2011)

- A filamentous bacterium called Streptomyces lincolnensis that produces lincomycin (progenitor of the lincosamide class of antibacterial drugs, e.g. clindamycin (Cleocin)) was isolated from soil collected in - you guessed it - Lincoln, Nebraska, United States (Geddes et al., 1964; Ball et al., 1978)

- A filamentous bacterium called Streptomyces fradiae (fradiae refers to Fradia, the given name of the mother of Selman Waksman, the researcher who discovered the bacterium) that produces the antibacterial drug neomycin (trade name Mycifradin) was isolated from adobe (clay) soil collected somewhere in New Jersey, United States (Waksman and Lechevalier, 1949) (http://www.bacterio.net/streptomycesb.html)

- A filamentous bacterium called Steptomyces griseus (griseus = grey, referring the grey colour of its colonies when grown on certain solid media) that produces the antibacterial drug streptomycin was isolated from both (a) soil collected from a heavily manured field and (b) the throat of a chicken somewhere in New Jersey, United States but probably near or at Rutgers University where the discoverers worked (Schatz et al., 1944; Waksman et al., 1948)

- A filamentous bacterium called Streptomyces cattleya (cattleya refers to the orchid genus of the same name, specifically the orchid-like purplish pink pigmentation of its aerial spore-bearing mycelium) that produces thienamycin (though it is itself highly unstable and so not used clinically, is the progenitor of the carbapenem class of antibacterial drugs, e.g. imipenem (Primaxin)) was isolated from soil collected somewhere in New Jersey, United States (Kahan et al., 1979; Papp-Wallace et al., 2011)

Italian poster extolling the virtues of
Streptomyces cattleya (Source)

- A bacterium called Bacillus subtilis (subtilis = slender, referring to the slender rod-like shape of its cells) that produces the antibacterial drug (mixture) bacitracin was isolated from damaged tissue excised from the badly broken and infected leg of a young girl named Margaret Tracy (after whom the drug was named) while she was being treated at Columbia University Medical Center in New York, New York, United States (Johnson et al., 1945)

- A filamentous bacterium called Micromonospora echinospora (echinospora = spiny spore) that produces the antibacterial drug gentamicin was isolated from loam (soil) collected in Syracuse, New York, United States (Weinstein et al., 1963; Kasai et al., 2000)

- A filamentous bacterium called Streptomyces spectabilis (spectabilis = visible/notable/remarkable, referring to its production of distinctive reddish orange pigments) that produces the antibacterial drug spectinomycin (also known as actinospectacin) (trade name Trobicin) was isolated from soil collected in Dallas, Texas, United States (Mason et al., 1961; Dietz et al., 1963)

- A filamentous bacterium called Streptomyces niveus (niveus = snow-white, referring to the white colour of its aerial spore-bearing mycelium) that produces the antibacterial drug novobiocin (also known as streptonivicin) was isolated from soil collected from an old sod pasture in Vermont, United States (Smith et al., 1956; Hyman, 1962; Tamura et al., 2008)

- A filamentous bacterium called Streptomyces noursei that produces the antifungal drug nystatin (named after New York State) (also known as fungicidin) was isolated from soil collected near the barn of a dairy farm (noursei refers to the owner of the farm, William Nourse) in Fauquier County, Virginia, United States (Hazen and Brown, 1951; Bacon, 1976; Espinel-Ingroff, 2003)

- A filamentous bacterium called Streptoalloteichus tenebrarius (tenebrarius = belonging to darkness, referring to the light sensitivity of the bacterium) that produces the antibacterial drug tobramycin (also known as nebramycin factor 6, since it is derived from nebramycin, a complex of aminoglycosides) was isolated from soil collected in Hermosillo, a city in Sonora, a state in northwestern Mexico (Higgins and Kastner, 1967; Tamura et al., 2008)

South America

- A filamentous bacterium called Streptomyces rimosus forma paromomycinus (which apparently later became known as Streptomyces krestomuceticus) that produces the antibacterial and antiparasitic drug paromomycin (trade name Humatin) was isolated from soil collected at Tierradura, an estate in the town of Miranda in Cauca, a department in southwestern Colombia (Frohardt et al., 1959; Davidson et al., 2009)

- A filamentous bacterium called Streptomyces venezuelae that produces the antibacterial drug chloramphenicol was isolated from mulched soil collected near Caracas, the capital city of Venezuela (Meissner and Smith, 1979)

- A filamentous bacterium called Streptomyces nodosus (nodosus = full of knots, referring to the tightly knotted coils formed by its spore chains) that produces the antifungal drug amphotericin B was isolated from rotting vegetation collected somewhere along the banks of the Orinoco River in Venezuela (Trejo and Bennett, 1963; Armstrong and Schmitt, 1990)

- A filamentous bacterium called Streptomyces pristinaespiralis (pristinaespiralis = primitive/early spiraled, possibly referring to the irregular spirals formed by its spore chains???) that produces the antibacterial drug pristinamycin (trade names Synercid and Pyostacine) was isolated from soil collected at San Carlos Minas, a town in Córdoba Province, Argentina (Mancy et al., 1964; Jolles et al., 1965)

- A filamentous bacterium called Streptomyces clavuligerus (clavuligerus = bearing little clubs, referring to the club-like morphology of its spores) that produces the β-lactamase inhibitor clavulanic acid was isolated from soil collected somewhere in South America (Higgens and Kastner, 1971; Reading and Cole, 1977)

Europe

- A filamentous fungus called Tolypocladium inflatum that produces the immunosuppressive drug ciclosporin (cyclosporine) (trade names Neoral and Sandimmune) was isolated from soil collected at the edge of a road (Rv7) in Hardangervidda, an arctic mountain plateau in central southern Norway (Svarstad et al., 2000)

- A bacterium called Pseudomonas fluorescens (fluorescens refers to its production of fluorescent pigments, causing it to glow under UV light) that produces the antibacterial drug mupirocin (also known as pseudomonic acid) was isolated from soil collected at Hampstead Heath, a large park in London, England (Fuller et al., 1971)

- A filamentous bacterium called Streptomyces ambofaciens (ambofaciens = producing both, referring to its production of two different drugs) that produces the antibacterial and antiparasitic drug spiramycin (trade name Rovamycine) was isolated from soil collected somewhere in northern France (Hays and Speer, 1960; Montoya and Remington, 2008) (http://www.bacterio.net/streptomycesa.html)

- A filamentous bacterium called Amycolatopsis rifamycinica that produces rifamycin B (both the bacterium and the drug are named after a classic French film that was popular at the time of their discovery) (progenitor of the rifamycin class of antibacterial drugs, e.g. rifampicin/rifampin (Rifadin)) was isolated from soil collected in a pine forest near the town of Saint-Raphaël in southeastern France along the Mediterranean coast (Margalith and Beretta, 1960; Bala et al., 2004)

- A filamentous bacterium called Streptomyces peucetius (peucetius refers to the Peucetii, a tribe that preceded the Romans in the region of Italy where the bacterium was isolated) (Peucetia is an ancient name for central Apulia) that produces the anticancer drug daunorubicin (refers to the Dauni, a tribe that lived in the same regions as the Peucetii where S. peucetius was isolated, and rubis, the French word for ruby because of the red colour of the drug) (doxorubicin, a similar drug that eventually replaced daunorubicin, was derived from an intentionally mutated strain of S. peucetius) was isolated from soil collected near the Castel del Monte, a small 13th-century castle and World Heritage Site in the Apulia region of southeast Italy (Weiss, 1992)

Castel del Monte (Source)

- A filamentous fungus called Penicillium stoloniferum (stoloniferum refers to having stolons, or hyphae that connect its spore-forming branches together?) that produces the immunosuppressive drug mycophenolic acid (mycophenolate) was isolated from corn infected by the fungus growing somewhere in Italy (Bentley, 2000)

- A filamentous fungus called Acremonium chrysogenum (chrysogenum = gold producing, referring to its production of bright yellow pigment) that produces cephalosporin C (progenitor of the cephalosporin class of antibacterial drugs, e.g. cefalexin/cephalexin (Keflex)) (named after the original genus assigned to the mould, Cephalosporium) was isolated from seawater near a sewage outflow on the coast of Sardinia, an island belonging to Italy in the Mediterranean Sea (Murdoch et al., 1964; Abraham, 1979; Rehner and Samuels, 1995)

- A filamentous fungus called Glarea lozoyensis that produces pneumocandin B0 (itself not used clinically, precursor to the antifungal drug caspofungin (trade name Cancidas)) was isolated from "filtrates of water and sediments from a farm pond in the Valle del Rio Lozoya, near Madrid, Spain" (Schwartz et al., 1992; Bills et al., 1999; Vicente et al., 2003)

Africa

- A filamentous bacterium called Actinoplanes sp. SE50 (CBS 961.70) that produces acarbose (trade names Glucobay, Prandase, and Precose), an alpha-glucosidase inhibitor used to treat diabetes mellitus type 2, was isolated from soil collected at a coffee plantation near Ruiru, a city in central southern Kenya (Schwientek, 2012)

- A filamentous bacterium called Streptomyces natalensis that produces the antifungal drug natamycin (also known as pimaricin) was isolated from soil collected in Pietermaritzburg, a city in KwaZulu-Natal (natalensis refers to Natal), a province in South Africa (Struyk and Waisvisz, 1975)

- cyanobacteria of the genera Symploca and Lyngbya that produce dolastatin 10 (from which monomethyl auristatin E, which is attached to antibodies to make the drugs brentuximab vedotin and glembatumumab vedotin, was derived) were isolated from Dolabella auricularia (a large sea slug/hare that feeds upon the cyanobacteria) found in the western Indian Ocean in shallow waters (1-2 m deep) off the eastern coast of Mauritius (Pettit et al., 1993; Simmons et al., 2008)

Dolabella auricularia sea slug (Source)

Asia

- A filamentous bacterium called Streptomyces roseosporus (roseosporus = rosy-spored, referring to the pink colour of its aerial spore-bearing mycelium) that produces the antibacterial drug daptomycin (trade name Cubicin) was isolated from soil collected on Mount Ararat, a dormant volcano in Turkey near its border with Iran (Eaton et al., 1989)

Mount Ararat (Source)

- A filamentous bacterium called Actinoplanes deccanensis (deccanensis refers to Decca, where it was isolated) that produces the antibacterial drug fidaxomicin (also known as lipiarmycin) (trade names Dificid and Dificlir) was isolated from soil collected somewhere in northern India (original paper states it was isolated from soil collected at "locality Decca in India" - Decca is apparently an alternate spelling of Dhaka, which refers to several locations in northern India???) (Parenti et al., 1975)

- A filamentous bacterium called Actinoplanes teichomyceticus (teichomyceticus = belonging to a fungus cell wall, referring to its inhibition of cell wall formation) that produces the antibacterial drug teicoplanin (also known as teichomycin) (trade name Targocid) was isolated from soil collected in Indore, a city in Madhya Pradesh, a state in central India (Parenti et al., 1978)

- A filamentous bacterium called Amycolatopsis orientalis that produces the antibacterial drug vancomycin (trade name Vancocin) was isolated from soil collected along a path in a rainforest in Borneo, an island (third-largest in the world) in Asia (orientalis = of the orient) shared among Brunei, Malaysia, and Indonesia, by a Christian and Missionary Alliance missionary by the name of Rev. William M. Bouw (McGraw, 1974; Lechevalier et al., 1986; Levine, 2006)

- A filamentous bacterium called Saccharopolyspora erythraea (erythraea = reddish, referring to the reddish brown colour of its colonies when grown on certain solid media) that produces the antibacterial erythromycin A (trade name Ilosone) was isolated from soil collected in Iloilo City, located along the southern coast of Panay, an island in the Philippines (Bunch and Mcguire, 1953; Livingood et al., 1953; Labeda, 1987)

- A filamentous bacterium called Streptomyces verticillus (verticillus = spindle whorl, referring to the coiled arrangement of its aerial mycelium) that produces the anticancer drug bleomycin (trade name Blenoxane) was isolated from soil collected from a coal mine in Kaho, a district in Fukuoka Prefecture, Japan (Umezawa et al., 1966; Umezawa et al., 1972)

- A filamentous fungus called Coleophoma empetri F-11899 that produces FR901379 (itself not used clinically, precursor to the antifungal drug micafungin (Mycamine)) was isolated from soil collected in Iwaki, a city in Fukushima Prefecture, Japan (Iwamoto et al., 1994; Yamada et al., 2009)

- A filamentous bacterium called Streptomyces tsukubaensis that produces the immunosuppressive drug tacrolimus (also known as FK-506 and fujimycin) (trade names Advagraf, Prograf, and Protopic) was isolated from soil collected in Tsukuba (tsukubaensis refers to Tsukuba), a city in Ibaraki Prefecture, Japan (where the drug company the researchers who isolated the bacterium worked?) (Kino et al., 1987; Okuhara et al., 1990; Barreiro et al., 2012)

- A filamentous bacterium called Streptomyces carzinostaticus (carzinostaticus = ???) that produces neocarzinostatin (precursor to the anticancer drug zinostatin stimalamer) was isolated from soil collected in Sendai, the capital city of Miyagi Prefecture, Japan (Ishida et al., 1965)

- A filamentous bacterium called Streptomyces kanamyceticus that produces the antibacterial drug kanamycin A (also known as just plain ol' kanamycin) was isolated from soil collected somewhere in Nagano Prefecture, Japan (Umezawa, 1958)

- A filamentous bacterium called Streptomyces avermectinius (formerly Streptomyces avermitilis) that produces avermectins (themselves not used clinically, but progenitors of the avermectin class of anthelmintic (antiparasitic) drugs, e.g. ivermectin) was isolated from soil collected near a reasonably famous golf course bordering the ocean in Kawana, in Ito, a city (hot spring resort town) on the eastern shore of the Izu Peninsula in Shizuoka Prefecture, Japan (Takahashi et al., 2002; Omura and Crump, 2004)

Kawana golf resort (Source)

- A bacterium called Brevibacillus laterosporus (laterosporus = side spore, referring to the presence of a distinctive canoe-shaped body attached to the side of its spores) that produces spergualin (precursor to the immunosuppressive drug gusperimus) was isolated from soil collected at Ōhira, a town in Shimotsuga District (now merged into the city of Tochigi), Tochigi Prefecture, Japan (Hannay, 1957; Takeuchi et al., 1981)

- A filamentous bacterium called Streptomyces ardus (ardus = dry/withered/meager, referring to its limited spore production) (also known as Streptomyces caespitosus) that produces the anticancer drug mitomycin C (trade names Mitozytrex and Mutamycin) was isolated from soil collected in Shibuya, a special ward (downtown municipality) of Tokyo, Japan (Hata and Sugawara, 1956) (Hatano et al., 2003)

- A filamentous bacterium called Streptomyces galilaeus (galilaeus refers to Galilee, apparently the source of the soil from which the type strain of this species was isolated) that produces the anticancer drug aclarubicin (also known as aclacinomycin A) was isolated from soil collected in the Osaki district (near the institute where the scientists who isolated the bacterium worked) of Shinagawa, a special ward (downtown municipality) of Tokyo, Japan (Umezawa et al., 1976) (http://www.bacterio.net/streptomycesb.html)

- A bacterium called Chromobacterium violaceum (violaceum = violet coloured, referring to its production of a violet pigment) that produces the anticancer drug (histone deacetylase inhibitor) romidepsin (also known as depsipeptide, FK228, and FR901228) (trade name Istodax) was isolated from a soil sample collected somewhere in Yamagata Prefecture, Japan (Ueda et al., 1994)

Oceania

- A filamentous bacterium called Streptomyces hygroscopicus (hygroscopicus refers to the hygroscopic nature of the bacterium, i.e. it readily takes up and retains moisture, forming gelatinous spore-filled spots on solid growth media) that produces the immunosuppressive drug rapamycin (refers to Rapa Nui, another name for Easter Island, where the bacterium was isolated) (also known as sirolimus) (trade name Rapamune) was isolated from soil collected at Rapa Nui (Easter Island), a Polynesian island that is part of Chile (Vézina et al., 1975)


References

Abraham EP. 1979. A glimpse of the early history of the cephalosporins. Reviews of Infectious Diseases 1(1):99-105.

Armstrong D, Schmitt HJ. 1990. Older drugs. In: Chemotherapy of Fungal Diseases, Handbook of Experimental Pharmacology Volume 96. Springer.

Bacon WS. 1976. Elizabeth Lee Hazen 1885-1975. Mycologia 68(5):961-969.

Bala S, Khanna R, Dadhwal M, Prabagaran SR, Shivaji S, Cullum J, Lal R. 2004. Reclassification of Amycolatopsis mediterranei DSM 46095 as Amycolatopsis rifamycinica sp. nov. International Journal of Systematic and Evolutionary Microbiology 54(Pt 4):1145-1149. [Full text]

Ball AP, Gray JA, Murdoch JMC. 1978. Lincomycin and Clindamycin. In: Antibacterial Drugs Today. Springer, 1978. Pp. 44-46.

Barreiro C, Prieto C, Sola-Landa A, Solera E, Martínez-Castro M, Pérez-Redondo R, García-Estrada C, Aparicio JF, Fernández-Martínez LT, Santos-Aberturas J, Salehi-Najafabadi Z, Rodríguez-García A, Tauch A, Martín JF. 2012. Draft genome of Streptomyces tsukubaensis NRRL 18488, the producer of the clinically important immunosuppressant tacrolimus (FK506). Journal of Bacteriology 194(14):3756-3757. [Full text]

Bentley R. 2000. Mycophenolic acid: a one hundred year odyssey from antibiotic to immunosuppressant. Chemical Reviews 100(10):3801-3826.

Bergy ME, De Boer C, Dietz A, Eble TE, Herr RR, Johnson LE. 1962. Streptozotocin and its production U.S. Patent 3027300.

Bills GF, Platas G, Peláez F, Masurekar P. 1999. Reclassification of a pneumocandin-producing anamorph, Glarea lozoyensis gen. et sp. nov., previously identified as Zalerion arboricola. Mycological Research 103(2):179-192.

Bunch RL, Mcguire JM. 1953. Erythromycin, its salts, and method of preparation. U.S. Patent 2653899.

Davidson RN, den Boer M, Ritmeijer K. 2009. Paromomycin. Transactions of the Royal Society of Tropical Medicine and Hygiene 103(7):653-660.

Desoubeaux G, Maakaroun-Vermesse Z, Lier C, Bailly E, Morio F, Labarthe F, Bernard L, Chandenier J. 2013. Successful treatment with fumagillin of the first pediatric case of digestive microsporidiosis in a liver-kidney transplant. Transplant Infectious Disease 15(6):E250-E259.

Dietz A, de Boer C, Smith RM, Siminoff P, Boyack GA, Whitfield GB. 1963. Antibiotic streptovaricin and process for its production. U.S. Patent 3116202.

Duggar BM. 1948. Aureomycin; a product of the continuing search for new antibiotics. Annals of the New York Academy of Sciences 51(2):177-181.

Eaton TE, Ford LM, Godfrey OW, Huber MLB, Zmijewski MJ. 1989. Process for producing the A-21978C antibiotics. U.S. Patent 4800157.

Espinel-Ingroff AV. 2003. The advent of antifungal and immunosuppressive therapies: 1950 to 1969. In: Medical Mycology in the United States. Springer.

Finlay AC, Hobby GL, P'an SY, Regna PP, Routien JB, Seeley DB, Shull GM, Sobin BA, Solomons IA, Vinson JW, Kane JH. 1950. Terramycin, a new antibiotic. Science 111(2874):85.

Frohardt RP, Haskell TH, Ehrlich J, Knudsen MP. 1959. Antibiotic and methods for obtaining same. U.S. Patent 2916485.

Fuller AT, Mellows G, Woolford M, Banks GT, Barrow KD, Chain EB. 1971. Pseudomonic acid: an antibiotic produced by Pseudomonas fluorescens. Nature 234(5329):416-417.

Geddes AM, Sleet RA, Murdoch JMC. 1964. Lincomycin hydrochloride: Clinical and laboratory studies. British Medical Journal 5410:670-672. [Full text]

Groth I, Schütze B, Boettcher T, Pullen CB, Rodriguez C, Leistner E, Goodfellow M. 2003. Kitasatospora putterlickiae sp. nov., isolated from rhizosphere soil, transfer of Streptomyces kifunensis to the genus Kitasatospora as Kitasatospora kifunensis comb. nov., and emended description of Streptomyces aureofaciens Duggar 1948. International Journal of Systematic and Evolutionary Microbiology 53(Pt 6):2033-2040. [Full text]

Hannay CL. 1957. The parasporal body of Bacillus laterosporus Laubach. The Journal of Biophysical and Biochemical Cytology 3(6):1001-1010. [Full text]

Hanson FR, Eble TE. 1953. Fumagillin and preparation. U.S. Patent 2652356.

Hata T, Sugawara R. 1956. Mitomycin, a new antibiotic from Streptomyces. II. Description of the strain. The Journal of Antibiotics (Tokyo) 9(4):147-151.

Hatano K, Nishii T, Kasai H. 2003. Taxonomic re-evaluation of whorl-forming Streptomyces (formerly Streptoverticillium) species by using phenotypes, DNA-DNA hybridization and sequences of gyrB, and proposal of Streptomyces luteireticuli (ex Katoh and Arai 1957) corrig., sp. nov., nom. rev.. International Journal of Systematic and Evolutionary Microbiology 53(Pt 5):1519-1529. [Full text]

Hays VW, Speer VC. 1960. Effect of spiramycin on growth and feed utilization of young pigs. Journal of Animal Science 19(3):938-942. [Full text]

Hazen EL, Brown R. 1951. Fungicidin, an antibiotic produced by a soil actinomycete. Experimental Biology and Medicine 76(1):93-97.

Higgins CE, Kastner RE. 1967. Nebramycin, a new broad-spectrum antibiotic complex. II. Description of Streptomyces tenebrarius. Antimicrobial Agents and Chemotherapy 7:324-331.

Higgens CE, Kastner RE. 1971. Streptomyces clavuligerus sp. nov., a β-lactam antibiotic producer. International Journal of Systematic and Evolutionary Microbiology 21(4):326-331. [Full text]

Hoeprich PD. 1968. The penicillins, old and new. Review and perspectives. California Medicine 109(4):301-308. [Full text]

Hyman W. 1962. Antibiotic and process of producing the same. U.S. Patent 3049534.

Ishida N, Miyazaki K, Kumagai K, Rikimaru M. 1965. Neocarzinostatin, an antitumor antibiotic of high molecular weight. Isolation, physicochemical properties and biological activities. The Journal of Antibiotics (Tokyo) 18:68-76.

Iwamoto T, Fujie A, Sakamoto K, Tsurumi Y, Shigematsu N, Yamashita M, Hashimoto S, Okuhara M, Kohsaka M. 1994. WF11899A, B and C, novel antifungal lipopeptides. I. Taxonomy, fermentation, isolation and physico-chemical properties. The Journal of Antibiotics (Tokyo) 47(10):1084-1091. [Full text]

Johnson BA, Anker H, Meleney FL. 1945. Bacitracin: a new antibiotic produced by a member of the Bsubtilis group. Science 102(2650):376-377.

Jolles F, Terlain B, Thomas JP. 1965. Metabolic investigations on pristinamycin. Nature 207(993):199-200.

Jukes TH. 1985. Some historical notes on chlortetracycline. Reviews of Infectious Diseases 7(5):702-707.

Kahan JS, Kahan FM, Goegelman R, Currie SA, Jackson M, Stapley EO, Miller TW, Miller AK, Hendlin D, Mochales S, Hernandez S, Woodruff HB, Birnbaum J. 1979. Thienamycin, a new beta-lactam antibiotic. I. Discovery, taxonomy, isolation and physical properties. The Journal of Antibiotics (Tokyo) 32(1):1-12. [Full text]

Kasai H, Tamura T, Harayama S. 2000. Intrageneric relationships among Micromonospora species deduced from gyrB-based phylogeny and DNA relatedness. International Journal of Systematic and Evolutionary Microbiology 50(Pt 1):127-134. [Full text]

Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H. 1987. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. The Journal of Antibiotics (Tokyo) 40(9):1249-1255. [Full text]

Labeda DP. 1987. Transfer of the Type Strain of Streptomyces erythraeus (Waksman 1923) Waksman and Henrici 1948 to the Genus Saccharopolyspora Lacey and Goodfellow 1975 as Saccharopolyspora erythraea sp. nov., and Designation of a Neotype Strain for Streptomyces erythraeus. International Journal of Systematic and Evolutionary Microbiology 37(1):19-22. [Full text]

Lechevalier MP, Prauser H, Labeda DP, Ruan JS. 1986. Two new genera of nocardioform actinomycetes: Amycolata gen. nov. and Amycolatopsis gen. nov. International Journal of Systematic and Evolutionary Microbiology 36(1):29-37.

Levine DP. 2006. Vancomycin: a history. Clinical Infectious Diseases 42 Suppl 1: S5-12. [Full text]

Livingood CS, Head ES, Johnson ES, Nilasena S. 1953. Erythromycin in local treatment of cutaneous bacterial infections. Journal of the American Medical Association 53(14):1266-1270.

Mancy DI, Ninet L, Preud'Homme J. 1964. Process for the production of pristinamycin. U.S. Patent 3154475.

Margalith P, Beretta G. 1960. Rifomycin. XI. Taxonomic study on Streptomyces mediterranei nov. sp. Mycopathologia et Mycologia Applicata 13(4):321-330.

Mason DJ, Dietz A, Smith RM. 1961. Actinospectacin, a new antibiotic. I. Discovery and biological properties. Antibiotics and Chemotherapy 11:118-122.

McCowen MC, Callender ME, Lawlis JF. 1951. Fumagillin (H-3), a new antibiotic with amebicidal properties. Science 113(2930):202-203.

McGraw DJ. 1974. The antibiotic discovery era (1940-1960): Vancomycin as an example of the era. Ph.D. Thesis. Oregon State University, USA. [Full text]

Meissner HC, Smith AL. 1979. The current status of chloramphenicol. Pediatrics 64(3):348-356.

Montoya JG, Remington JS. 2008 Management of Toxoplasma gondii infection during pregnancy. Clinical Infectious Diseases 47(4):554-566. [Full text]

Murdoch JMC, Speirs CF, Geddes AM, Wallace ET. 1964. Clinical trial of cephaloridine (Ceporin), a new broad-spectrum antibiotic derived from cephalosporin C. British Medical Journal 2(5419): 1238-1240. [Full text]

Nelson ML, Levy SB. 2011. The history of the tetracyclines. Annals of the New York Academy of Sciences 1241:17-32.

Okuhara M, Tanaka H, Goto T, Kino T, Hatanaka H. 1990. Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same. U.S. Patent 4956352.

Omura S, Crump A. 2004. The life and times of ivermectin - a success story. Nature Reviews. Microbiology. 2(12):984-989.

Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA. 2011. Carbapenems: past, present, and future. Antimicrobial Agents and Chemotherapy 55(11):4943-4960. [Full text]

Parenti F, Pagani H, Beretta G. 1975. Lipiarmycin, a new antibiotic from Actinoplanes. I. Description of the producer strain and fermentation studies. The Journal of Antibiotics (Tokyo) 28(4):247-252. [Full text]

Parenti F, Beretta G, Berti M, Arioli V. 1978. Teichomycins, new antibiotics from Actinoplanes teichomyceticus nov. sp. I. Description of the producer strain, fermentation studies and biological properties. The Journal of Antibiotics (Tokyo) 31(4):276-283. [Full text]

Pettit GR, Kamano Y, Herald CL, Fujii Y, Kizu H, Boyd MR, Boettner FE, Doubek DL, Schmidt JM, Chapuis JC, Michel C. 1993. Isolation of dolastatins 10-15 from the marine mollusc Dolabella auricularia. Tetrahedron 49(41):9151-9170.

Raper KB. 1946. The development of improved penicillin-producing molds. Annals of the New York Academy of Sciences 48(2):41-56.

Reading C, Cole M. 1977. Clavulanic acid: a beta-lactamase-inhibiting beta-lactam from Streptomyces clavuligerus. Antimicrobial Agents and Chemotherapy 11(5):852-857. [Full text]

Rehner SA, Samuels GJ. 1995. Molecular systematics of the Hypocreales: a teleomorph gene phylogeny and the status of their anamorphs. Canadian Journal of Botany 73(S1):816-823.

Schatz A, Bugle E, Waksman SA. 1944. Streptomycin, a substance exhibiting antibiotic activity against Gram-positive and Gram-negative bacteria. Experimental Biology and Medicine 55(1):66-69.

Schwartz RE, Sesin DF, Joshua H, Wilson KE, Kempf AJ, Goklen KA, Kuehner D, Gailliot P, Gleason C, White R, Inamine E, Bills G, Salmon P, Zitano L. 1992. Pneumocandins from Zalerion arboricola. I. Discovery and isolation. The Journal of Antibiotics (Tokyo) 45(12):1853-1866. [Full text]

Schwientek P. 2012. Genomics and transcriptomics of the industrial acarbose producer Actinoplanes sp. SE50/110. Ph.D. Thesis. Bielefeld University, Germany. [Full text]

Simmons TL, Coates RC, Clark BR, Engene N, Gonzalez D, Esquenazi E, Dorrestein PC, Gerwick WH. 2008. Biosynthetic origin of natural products isolated from marine microorganism-invertebrate assemblages. Proceedings of the National Academy of Sciences USA 105(12):4587-4594. [Full text]

Smith CG, Dietz A, Sokolski WT, Savage GM. 1956. Streptonivicin, a new antibiotic. I. Discovery and biologic studies. Antibiotics and Chemotherapy 6(2):135-142.

Struyk AP, Waisvisz JM. 1975. Pimaricin and process of producing same. U.S. Patent 3892850.

Svarstad H, Bugge HC, Dhillion SS. 2000. From Norway to Novartis: Cyclosporin from Tolypocladium inflatum in an open access bioprospecting regime. Biodiversity and Conservation 9:1521-1541.

Takahashi Y, Matsumoto A, Seino A, Ueno J, Iwai Y, Omura S. 2002. Streptomyces avermectinius sp. nov., an avermectin-producing strain. International Journal of Systematic and Evolutionary Microbiology 52(Pt 6):2163-2168. [Full text]

Takeuchi T, Iinuma H, Kunimoto S, Masuda T, Ishizuka M, Takeuchi M, Hamada M, Naganawa H, Kondo S, Umezawa H. 1981. A new antitumor antibiotic, spergualin: isolation and antitumor activity. The Journal of Antibiotics (Tokyo) 34(12):1619-1621. [Full text]

Tamura T, Ishida Y, Otoguro M, Hatano K, Suzuki K. 2008. Classification of ‘Streptomyces tenebrarius’ Higgins and Kastner as Streptoalloteichus tenebrarius nom. rev., comb. nov., and emended description of the genus Streptoalloteichus. International Journal of Systematic and Evolutionary Microbiology 58(Pt 3):688-691. [Full text]

Tamura T, Ishida Y, Otoguro M, Hatano K, Labeda D, Price NP, Suzuki K. 2008. Reclassification of Streptomyces caeruleus as a synonym of Actinoalloteichus cyanogriseus and reclassification of Streptomyces spheroides and Streptomyces laceyi as later synonyms of Streptomyces niveus. International Journal of Systematic and Evolutionary Microbiology 58(Pt 12):2812-2814. [Full text]

Trejo WH, Bennett RE. 1963. Streptomyces nodosus sp. n., the amphotericin-producing organism. Journal of Bacteriology 85(2):436-439. [Full text]

Ueda H, Nakajima H, Hori Y, Fujita T, Nishimura M, Goto T, Okuhara M. 1994. FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity. The Journal of Antibiotics (Tokyo) 47(3):301-310. [Full text]

Umezawa H. 1958. Kanamycin: its discovery. Annals of the New York Academy of Sciences 76(2):20-26.

Umezawa H, Maeda K, Takeuchi T, Okami Y. 1966. New antibiotics, bleomycin A and B. The Journal of Antibiotics (Tokyo) 19(5):200-209.

Umezawa H, Maeda K, Okami Y, Takeuchi T. 1972. Bleomycin and processes for the preparation thereof. U.S. Patent 3681491.

Umezawa H, Takeuchi T, Hamada M, Takamatsu A, Oki T. 1976. Antibiotics aclacinomycins A and B. U.S. Patent 3988315.

Vézina 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. The Journal of Antibiotics (Tokyo) 28(10):721-726. [Full text]

Vicente MF, Basilio A, Cabello A, Peláez F. 2003. Microbial natural products as a source of antifungals. Clinical Microbiology and Infection 9(1):15-32. [Full text]

Waksman SA, Reilly HC, Harris DA. 1948. Streptomyces griseus (Krainsky) Waksman and Henrici. Journal of Bacteriology 56(3):259–269. [Full text]

Waksman SA, Lechevalier HA. 1949. Neomycin, a new antibiotic active against streptomycin-resistant bacteria, including tuberculosis organisms. Science 109(2830):305-307.

Weinstein MJ, Luedemann GM, Oden EM, Wagman GH, Rosselet JP, Marquez JA, Coniglio CT, Charney W, Herzog HL, Black J. 1963. Gentamicin, a new antibiotic complex from Micromonospora. Journal of Medicinal Chemistry 6(4):463-464.

Weiss RB. 1992. The anthracyclines: will we ever find a better doxorubicin? Seminars in Oncology 19(6):670-686.

Yamada M, Yawata K, Orino Y, Ueda S, Isogai Y, Taguchi G, Shimosaka M, Hashimoto S. 2009. Agrobacterium tumefaciens-mediated transformation of antifungal-lipopeptide-producing fungus Coleophoma empetri F-11899. Current Genetics 55(6):623-630.

No comments:

Post a Comment