ANTIBACTERIAL SUBSTANCES FROM MOULDS 175 



Another tjrpe of gramicidin. Gramicidin S, has been derived from an unidentified 

 spore-bearing bacillus by Gause and Brazhnikova (1944). It is reported to be more 

 active than tyrothricin against streptococci and pneumococci ; and, when locally apphed, 

 to be curative in suppurative infections of man, especially those due to Staph, aureus. 



Antibacterial Substances from Moulds. 



Among the moulds the Actinomycetes, the Penicillia and the Aspergilli have 

 yielded antibacterial agents of various kinds. Wilkins and Harris (1942, 1943a), 

 in an examination of 200 mould cultures for inhibitors of Staph, aureus, Bad. coli 

 and Ps. pyocyanea, record the greatest number of successes in the Penicillia and 

 Aspergilli, few in Phycomycetes and Ascomycetes. Inhibitors of the staphylococcus 

 were the most common, those of the Gram-negative bacilli less common. Atkinson 

 (1943rt) found a number of active strains among Penicillia, and few among Aspergilli, 

 Mucor and " pink moulds." The same substance may be produced by several 

 distinct species of mould (see, for example, White 1943, McKee and MacPhillamy 

 1943, Florey et al. 1944, Waksman 1944). One mould may produce several kinds 

 of antibacterial substance (see, for example, Waksman and Bugie 1943, Waksman 

 and Geiger 1944), and not all members of a species necessarily produce the same 

 substance, or produce it at all. 



One of the first mould-products to be applied to the treatment of infections 

 was an extract of a Streptothrix-like white mould, from which Gratia and Dath 

 (1924, 1925, 1926) were able, by growth on dead Staph, aureus, to produce a powerful 

 lytic agent for living Staph, aureus and other bacteria. They also noted lytic 

 agents for intestinal coliform bacilli in another white mould, and for B. anthracis 

 from an undetermined strain of Penicillium (see also Lieske 1921). The first 

 agent, which they termed a mycolysate, was employed, together with a staphylo- 

 coccal bacteriophage, in the successful treatment of Staph, aureus carbuncles in 

 man (Gratia and Dath 1930). 



In 1928 Fleming (1929) observed the suppression of growth of Staph, aureus 

 round a contaminating colony of a Penicillium that had grown on the agar plate. 

 The inhibitory substance, to which he gave the name penicillin, could be extracted 

 from cultures of the Penicillium, and proved active against Staph, aureus, Str. 

 pyogenes, the gonococcus, the meningococcus, and certain strains of Str. viridans. 

 The enterococcus, and Gram-negative organisms including Bact. friedldnderi, 

 H. influenzcB, Sh. flexneri and Past, pseudotuberculosis, were relatively insus- 

 ceptible. The crude filtrates of penicillin were non-toxic to leucocytes in anti- 

 bacterial concentrations. 



The combination of high antibacterial activity with low toxicity for leucocytes 

 led Fleming to suggest and test its application to local infection in man. The 

 amount of penicilUn in culture filtrates of the mould was, however, low, and owing 

 to its instability (Fleming 1932, Clutterbuck et al. 1932) attempts at that time to 

 concentrate it proved abortive. Not till Florey and his colleagues (see p. 179) 

 overcame the difficulties in its preparation and demonstrated its remarkable 

 therapeutic powers was its potential value in human medicine fully realized and an 

 active search begun for other similar products. 



Not all of the substances Hsted below have the qualities necessary for a suc- 

 cessful therapeutic agent. The curing dose is often so close to the tolerated dose 

 that therapy would be successful only under carefully controlled conditions, though 

 it is possible that some of the less well-defined mould products are mixtures of 

 an antibacterial agent and toxic materials which may later prove to be separable. 



