The Lord hath created medicines out of the earth and he that is

wise will not abhor them

ECCLESIASTICUS, XXX VIII

Quoted by Selman A. Waksman

in his Nobel Lecture, 1952

The Waksman Lab Actinomycin D – 1940 – Waksman and Woodruff

Streptomyces antibioticus – chromo oligopeptide Used for Wilm’s Tumor in children and a basic tool in

development of molecular biology as inhibitor of RNA polymerase

Streptomycin – 1945- Waksman and Schatz Streptomyces griseus – aminoglycoside First antibiotic against TB. Also vs. bacterial meningitis

Neomycin – 1948 – Waksman and Lechevalier Streptomyces fradiae – aminoglycoside - topical antibiotic

Candicidin – 1953 – Waksman and Lechevalier Streptomyces griseus – polyene antifungal

Another 25 antibiotics Waksman et al’s discoveries stimulated drug discovery

work internationally from 1948 until today

Use of Secondary Metabolites

Helped double lifespan in 20th century

Reduced pain and sufferingRevolutionized medicine by

facilitating organ transplantation(Verdine, 1996)

Facts About Secondary Metabolites

10,000 microbial secondary metabolites have been discovered.

Actinomycetes produce about 75% of all described antibiotics.

Streptomyces species make 75% of all actinomycete secondary metabolites.

Streptomyces hygroscopicus strains produce over 180 different secondary metabolites.

(Omura, 1992; Zedan, 1993; Miyadoh, 1993)

ANTI-INFECTIVE MARKET

1996:160 ANTIBIOTICS$23 BILLION MARKET

2000:$55 BILLION MARKET

BLOCKBUSTER MARKETS FOR NATURAL PRODUCT DERIVATIVESProduct $ billion

Cephalosporins 10

Lipitor 9.2

Zocor 6.2

Penicillins 6

Augmentin 2

Azithromycin 1.5

Clarithromycin 1.2

Rocephin 1.1

(Elander, 2002; Thayer, 2003; Strohl, 2004)

Clavulanic Acid

β-Lactamase inhibitor Market is over $1 billion Used in combination with susceptible

penicillins.

With amoxycillin=Augmentintm

With ticarcillin=Timentintm

(Jensen and Paradkar, 1999)

CARBAPENEMS

Thienamycin discovered in 1970’s. 40 naturally occurring forms, most from

Streptomyces. Broad spectrum antibiotics. Resistant to most β-lactamases.

(Derzelle et al., 2002)

GLYCOPEPTIDES

Sales of vancomycin and teicoplanin are $1 billion/year

(Williams and Bardsley, 1999)

DAPTOMYCIN Cyclolipopeptide produced by S. roseosporus Inhibits MRSA, VRE, penicillin-resistant

Streptococcus pneumoniae, linezolide-resistant bacteria.

Discovered by Lillyin early 1980’s. Licensed to Cubist in 1997. Approved in 2003 and licensed to Chiron. Disrupts plasma membrane function wothout

entering cytoplasm; unique mode of action. Bacteriocidal. First new natural antibiotic in many years.

(Tally et al., 1999; Raja et al., 2003)

ERYTHROMYCIN SALES ERYTHROMYCIN SALES AMOUNTED TO $3.0 AMOUNTED TO $3.0 BILLION IN 1998.BILLION IN 1998.

(McDaniel et al., 1999)(McDaniel et al., 1999)

Modified Erythromycins

Clarithromycin (Biaxin® developed by Taisho)

Azithromycin (Zithromax® developed byPliva)

Telithromycin (Cetek® developed by Aventis) acts against resistant strains.

(Henninger, 2003)

Current Antitumor Agents

DaunorubicinDoxorubicinBleomycinsMitomycin CTaxol

Mylotarg (Gemtuzmab Ozogamycin)

Toxic enediyne antitumor agent calicheamycin attached to a humanized monoclonal antibody.

Directs enediyne to CD 33 protein antigen expressed by AML cells.

In 2000, approved for acute myeloid leukemia (AML).

(Borman, 2000)

Rapamycin

Discovered as antifungal agent. Produced by Streptomyces hygroscopicus. Unusual nitrogen-containing triene macrolide

(polyketide) with very large 31-membered lactone ring. Has antitumor activity. Immunosuppressive potency somewhat greater than

FK-506 and 150X cyclosporin A. Toxicity less than cyclosporin A. Precursors: acetate, propionate, methionine,

pipecolate, shikimate.

THE TACROLIMUS (FK506) STORY

Almost abandoned as a transplant immunosuppressant by Fujisawa because of dose-associated toxicity.

Dr. Thomas Starzl (U. Pittsburgh) rescued it by using lower doses , realizing it was 30-100x more active than cyclosporin A.

Introduced in Japan in 1993; USA in 1994. Used for transplants of liver, heart, kidney, pancreas,

lung, intestines, and for prevention of graft-vs.-host disease.

Topically used against a topic dermatitis, a widespread skin disease.

(T. Amaya et al., 2002)

ACTINOMYCETE IMMUNOSUPPRESSANTS HAVE MANY ACTIVITIES

Approved for organ transplantation. Antifungal. Antitumor. Reversal of multidrug resistance in mammalian cells. Ascomycin is anti-inflammatory; SDZ ASM 981 in clinical

tests vs. atopic dermtitis, allergic contact dermatitis and psoriasis. Also FK506.

(Arceci et al., 1992; Carle et al., 2000; Lehne et al., 2002; Robert and Jarry, 2003)

Anti-parasitic Agents

2. Antihelmintic AgentsPreviously only synthetic agentsHygromycin, destomycin, myxin, etc. failed to competeAvermectins (S. avermitilis)

Non-toxicNon-antimicrobialMacrocyclic lactonesDo not inhibit protein synthesisInterfere with neurotransmission in invertebrates

1000x thiobenzole10x other syntheticsActive vs. nematode and arthropod parasites in sheep, cattle,

dogs, horses, swineIvermectin (22,23-dihydroavermectin B1)Also insecticidal

Bialaphos- A Herbicide

1972 – Zähner group discovers phosphinothricyl-Ala-Ala from S. viridochromogenes: antibiotic against Gm+ and Gm- bacteria and Botyritis cinerea

1973 – Independent discovery at Meiji Seiki of Bialaphos from S. hygroscopicus

Bialaphos = phosphinothricyl-Ala-Ala

Bialaphos is an herbicide with or without Ala-Ala

Bialaphos without Ala-Ala (= phosphinothricin) developed by Hoechst as herbicide (“glufosinate”)

Acarbose

α-Glycosidase Tetrasaccharide produced by Actinoplanes sp. Used for Type I and Type II diabetes Anti-glycosidase action delays uptake of glucose

into intestine.

(Copsey et al.,1999; Wehmeier and Pipersberg, 2004)

DESFERAL Desferri-ferrioxamine B Discovered as an antibiotic Fe (III)-Chelator from Streptomyces pilosus Non-Toxic Uses:

Iron overload (hemochromatosis) in acute iron intoxication

Iron overload from transfusions Iron overload in Thalassemia Aluminum overload in dialysis patients Metal-desferal complex eliminated from body via

kidneys.

LIPSTATIN, AN ENZYME INHIBITOR Produced by Streptomyces toxytricini. A pancreatic lipase inhibitor. Combats diabetes and obesity. Interferes with gastrointestinal absorption

of fat. Commercial product ORLISTAT is

tetrahydrolipstatin.

(Weibel et al., 1987)

The microbe has come of age…there is no field of human endeavor, whether it be in industry or in agriculture, whether it be in the preparation of foodstuffs or in connection with problems of shelter and clothing, whether it be in the conservation of human and animal health and the combating of disease, where the microbe does not play an important and often a dominant part.

~S.A. Waksman, 1942