18 



NATURE, FORMATION, AND ACTIVITIES 



bacteria, cocci, spirochetes, and other 

 organisms. 



In 19ol, Dubos and Avery incorporated 

 polysaccharides from the capsule of type III 

 pneumococci in soil. They isolated from the 

 soil a bacillus which, when grown in a 

 synthetic medium containing the poly- 

 saccharide as the source of carbon, elabo- 

 rated an enzyme that specifically attacked 

 the organism. This enzyme could protect 

 mice from a fatal dose of type III pneumo- 

 coccus. Dubos continued the soil enrichment 

 study by introducing living l)acteria into the 

 soil, rather than the capsular material alone. 

 From these enriched soils Dubos in 1938 

 isolated a strain of Bacillus brevis which 

 produced an antibiotic that he called tyro- 

 thricin. In 1940, Hotchkiss and Dubos 

 showed that tyrothricin was composed of 

 two active antibiotics, tyrocidine and grami- 

 cidin. Tyrothricin is active chiefly against 

 gram-positive bacteria and is used topically 

 in medicine. The tyrothricin complex 

 opened the field for bacterial polypeptides, 

 to be followed soon by bacitracin, polymyxin, 

 subtilin, and a variety of others. The prac- 

 tical importance of some of these is still not 

 fully recognized. Even though it is doul)tful 

 that the soil enrichment method was a 

 necessary step in the isolation of the active 

 strain of B. brevis, the work of Dubos showed 

 the value of systematic screening programs 

 in the search for antibiotics. 



Another blow to the chance isolation pro- 

 cedure f^f obtaining antibiotic-producing 

 strains was dealt at about the same time by 

 what could be called the Rutgers group of 

 investigators. Ever since 1936, the senior 

 author of this treatise had been interested in 

 antagonistic relationships among soil micro- 

 organisms. Actinomycetes often showed 

 themseh'es to have outstanding antimicro- 

 bial activity. In 1940, Waksman and Wood- 

 ruff reported the isolation of actinomycin, 

 the first actinomycete-produced antibiotic 

 to be obtained in a crvstalline form. After 



this discovery, the attention of the Rutgers 

 group turned to products of fungi, and 

 cku-acin, fumigacin, and chaetomin were 

 isolated. Actinomycetes were not forgotten, 

 however, and systematic screening programs 

 yielded, among others, streptothricin (1942), 

 and most important of all, streptomycin 

 (1944). Streptothricin was an interesting 

 substance. It was basic, stable, and water- 

 soluble; it was active against gram-negative 

 and gram-positi\'e bacteria, m^ycobacteria, 

 and fungi in vitro and in vivo; however, it 

 had a delayed toxicity that limited its use- 

 fulness. Streptomycin had the same general 

 chemical properties as streptothricin but 

 was less toxic; infections caused by gram- 

 negative and gram-positive bacteria and 

 mycobacteria responded to treatment with 

 this new drug. The chemotherapy of tuber- 

 culosis was finally made possible. 



The Modern Period 



The success of the screening methods of 

 the Rutgers group was partly responsible 

 for the scrutiny of the actinomycetes in 

 screening programs throughout the world. 

 The results were rewarding. Antibiotics were 

 isolated which are active not only against 

 gram-positive and gram-negative bacteria, 

 but also against rickettsiae and the psitta- 

 cosis-lymphogranuloma group of organisms. 

 These antibiotics include chloramphenicol 

 (1947), chlortetracycline (1948), oxytetra- 

 cycline (19o0), and tetracycline (1953). 

 Others were to come later, namely, the 

 macrolides erythromycin (1952), carbomy- 

 cin (1952), spiramycin (1954), and oleando- 

 mycin (1954). Still others, similar to strepto- 

 mycin in certain respects, have found a 

 place in chemotherapy; these included 

 neomycin (1949), viomycin (1951), and 

 kanamycin (1957). 



Antibiotics were also found which are 

 primarily antifungal, such as cycloheximide 

 (194(5), nystathi (1951), candicidin (1952), 



