16 



NATURE, FORMATION, AND ACTIVITIES 



was attracted to the antibiotic potentialities 

 of actinomycetes. Gasperini, in 1890, re- 

 ported that the organism Strcptothri.r Foer- 

 steri, isolated as a contaminant, was able to 

 lyse bacteria and fungi. It was also before the 

 turn of the century that the first antibiotic 

 was isolated in a crystalline form. From a 

 strain of PeniciUium, Gosio, in 189(>, isolated 

 and crystallized the antibiotic which was 

 later called mycophenolic acid. 



Laying the Foundation for Antibiotic 

 Research 



The first four decades of the present 

 century were characterized by marked ad- 

 vances in chemotherap3^ First came the 

 arsenicals that were shown to have activity 

 against trypanosomes. Ehrlich and his col- 

 laborators made a great number of chemical 

 derivatives of the first compound, atoxyl, in 

 the hope of finding a substance that would 

 retain the antimicrobial activity of atoxyl 

 but be less toxic to the animal body. In 1909, 

 the 606th compound was found to possess 

 the desired properties and was named 

 salvarsan. 



Starting from the fact that certain azo 

 dyes were kn^own to have bactericidal 

 effects in vitro, a group of chemists from the 

 Bayer laboratories in Germany synthesized 

 a large number of these compounds. These 

 were tested by Gerhard Domagk in mice 

 infected with hemolytic streptococci. In 

 1932, one of the dyes, prontosil, was found 

 to be effective iii vivo. Strangely enough, it 

 was active only in vivo. This was explained 

 in 1935 by Trefouel and his collaborators at 

 the Pasteur Institute. They showed that the 

 dye was split in the body, that sulfanilamide, 

 one of the products formed, was the active 

 portion of the molecule anfl that it was ac- 

 tive both in vitro and in vivo. Hundreds of 

 derivatives of sulfanilamide were sub- 

 sequently synthesized and tested in animals 

 (references to the above papers are given by 

 Albert, 1951). 



The extensive testing of arsenicals and 

 sulfa drugs led to the development of micro- 

 biological, pharmacological, and pharma- 

 ceutical methods necessary for the progress 

 of antibiotic research. 



During the first four decades of the 

 twentieth century, while spectacular work 

 was being done in the field of chemotherapy 

 with arsenicals and sulfa drugs, numerous 

 observations, similar to those made during 

 the nineteenth century, were published in 

 the field of microbial antagonism. Only the 

 most important developments will be dis- 

 cussed here. 



The pyocyanase of Iilmmerich and Low 

 (1899) was studied in experimental animals 

 and in human patients. P'or a short time 

 commercial preparations of pyocyanaise 

 were available in Germany and were used 

 mainly topically. The theory that pyo- 

 cyanase was an enzyme did not last long, 

 since lipoidal, heat-stable fractions of the 

 crude extract were found to have anti- 

 bacterial action. 



The fungal antibiotic isolated in pure 

 form by Gosio in 1896 was studied again in 

 1913 by Alsberg and Black, and later by 

 Clutterbuck et al. (1932, 1933). This anti- 

 biotic, the first to be isolated in a pure form, 

 is now virtually unknown. 



In any scientific climate, the minds of 

 men are molded by the prevailing ideas of 

 the time. During the first four decades of 

 the twentieth century, emphasis on en- 

 zymes and lytic phenomena was to hinder 

 the development of antibiotics. This is true 

 of the discovery of the Twort-d'Herelle 

 phenomenon in 1915-1916. As mentioned 

 previously, Gratia and his collaborators in 

 Belgium had studied the bacteriolytic 

 properties of actinomycetes. It should l)e 

 stressed that these authors were prol)at)ly 

 the first to use the product of an actino- 

 mycete in human therapy. The treatment 

 seems to ha\-e been used mainly for staphylo- 

 coccal infections and consisted of injecting 



