The development of antibiotics for the treatment of bacterial infections, which was critical during the war years of the early 1940s, changed the course of drug discovery efforts in the pharmaceutical industry. Following the pioneering experiments of Selman Waksman at Rutgers University on soil actinomycetes, pharmaceutical companies began the systematic evaluation of antibiotics produced by bacteria isolated from the soil. During the succeeding quarter century, often referred to as the
OH u Cl
OH u Cl
Rifamycin S Amphotericin B
FIGURE 6.3 Additional examples of antibiotics found during the "Golden Age of antibiotics discovery."
"Golden Age" of antibiotic discovery, all of the major classes of life-saving antibiotics were found. The previously illustrated penicillin, vancomycin, tetracycline, and erythromycin represent the progenitors of the most important classes of antibacterial agents still in use. Other examples of these wonderfully complex compounds are illustrated in Figure 6.3. Streptomycin, isolated by Waksman from Streptomyces griseus, was the first of the class of aminoglycoside antibiotics to be introduced into therapy. Chloramphenicol, rifamycin, and amphotericin were also discovered during this time and each has a valuable niche in modern chemotherapy.
In addition to antibiotics used for the treatment of microbial diseases, microbial products have been explored for a number of other therapeutic uses. Owing to the relative ease with which new organisms could be isolated from the environment and grown in culture, these provided versatile sources of new chemistry. Beginning in the 1960s these sources were employed for screening against other diseases, such as parasitic and fungal infections, as well as for the ability to differentially kill cancer cells. Notable among the antiparasitic compounds discovered in this way are the milbemy-cins. These polyketide-derived macrolides, produced by Streptomyces species, are exceptionally effective against several types of parasites that infect livestock. Compounds in the milbemycin class, e.g., ivermectin and moxidectin (Figure 6.4) have also found utility against the devastating human disease of river blindness caused by filarial worms, which is endemic to sub-Saharan Africa, and other tropical areas of the world.
Actinomycete-derived antibiotics with efficacy as anticancer agents have also been a major focus of screening programs (see Figure 6.5). Waksman once again discovered the first of these, actino-mycin D, from Streptomyces parvullus. Today, actinomycin has quite limited use, but it served as a prototype for the discovery of other antitumor or antibiotics. Doxorubicin, which interacts similarly with DNA, was isolated in the 1960s and remains an important component of typical chemotherapy regimes. Another early discovery from the Golden Age that remains in use today for chemotherapy is bleomycin. Bleomycin is a complex glycopeptide antibiotic produced by S. verticillus that induces DNA damage through oxidative reactions.
OCH3 O H
Ivermectin B1a FIGURE 6.4 Antiparasitic milbemycin analogs.
Pro Pro Sa^
Thr Thr hN^O O^NH
OCH3 o OH
OCH3 o OH
t h nh2
FIGURE 6.5 Cytotoxic antibiotics.
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