176 ANTIBACTERIAL SUBSTANCES FOR TREATMENT OF INFECTIONS 



The substances are nevertheless of great interest apart from their possible use 

 in therapy. Those with a selective action on certain bacterial species are useful 

 for incorporation iiato culture media for suppressing the growth of unwanted 

 bacteria (see Chapter 12) ; the properties of some of them afford an explanation 

 of microbial antagonisms observed in nature ; and, where their constitution is 

 known, many of the substances are valuable in relating antibacterial activity to 

 molecular structure, or as reagents for exploring the metabolism of the organisms 

 upon which they act. It is noteworthy that most of the substances with a high 

 therapeutic- index act predominantly or exclusively uf)on Gram-positive bacteria, 

 with the exception of streptothriciu. Those acting on both Gram-positive and 

 Gram-negative bacteria appear, like the antiseptics, to be general protoplasmic 

 poisons. None is predominantly or exclusively active against Gram-negative 

 bacteria. 



Numerical measurements of antibacterial powers, and of toxicity to animal 

 tissues afford only a crude means of comparing the various substances. Apart 

 from the varying criteria of a given type of activity, the measures are dependent 

 on the degree of purity of often undefined substances, the strains of bacteria tested, 

 the type of culture medium, and the animal or type of animal tissue employed. 

 It may, however, be said that most of the substances are bacteriostatic in con- 

 centrations lower than 1 : 5,000, and many are bactericidal in higher concen- 

 trations. 



For a general comparison of a number of these substances, with a number of 

 antiseptics, see Waksman and Woodruff (1942). 



Actinomycetin, The bacteriolytic substance produced by sporulating cultures of a 

 Streptothrix-Uke mould {Actinomyces albus) has already been mentioned (Gratia and 

 Dath 1924). Welsch (1936, 1937, 1938, 1939, 1940, Welsch and Elford 1937) has studied 

 the lysin, to which he gave the name actinomycetin, in some detail. It appeared to be 

 a proteolytic enzyme, and was inactivated by heating to 54°-69° C, by ultra-violet radia- 

 tion, and by strong acids. It induced bacteriolysis over a wide range of pH, with an 

 optimum at pH 7-5 to 8-5. Lysis appears to depend on at least two factors, a lethal 

 substance which kiUs the bacteria, and a bacteriolytic enzyme either from the Actinomyces, 

 or from the bacteria themselves (see also Welsch 1942). 



Actinomycin A and B. These substances were isolated from cultures of Actinomyces 

 antibioticus, a soil organism, by Waksman and Woodi'uff (1940rt, b, 1941). Staphylococci 

 and streptococci are inhibited in dilutions of over 1 : 2-5 x 10®, and Salmonella baciUi 

 in 1 : 25,000. 



Actinomycin A is a water-soluble, red pigment, with a molecular weight of about 

 800, and appears to be a polycyclic nitrogen compound, having a reversible redox system 

 of the quinone type (Waksman and Tishler 1942). It is both bactericidal and bacterio- 

 static, inhibiting Gram-positive organisms in a dilution of 1 : 10^, and Gram-negative 

 organisms at dilutions of 1 : 5,000 to 1 : 10^. It is active against aerobic and anaerobic 

 bacteria, and against certain fungi. Actinomycin A is highly toxic to animals. Doses, 

 either oral or parenteral, of 1 mgm. per kilogram body weight are lethal for mice, rats 

 and rabbits, the animals dying in 15-20 hours with respiratory failure. Post mortem 

 there are gross pathological changes in liver, kidney and spleen. Sublethal doses have 

 no protective effect in mice infected with Str. pyogenes or Type I pneumococci (Robinson 

 and Waksman 1942). Actinomycin A inhibits fibrinolysis by Sir. 'pyogenes, the pro- 

 duction of coagulase by Staph, aureus, but does not affect either tetanus or diphtheria 

 toxin (Neter 1942, 1943) or staphylococcal toxin (Blair and Hallman 1943). 



Actinomycin B is a water-insoluble substance. It is markedly bactericidal, but not 

 bacteriostatic, and is highly toxic to animals. 



