CHEMOTHERAPY 



have the usual /-configuration but, surprisingly, a considerable frac- 

 tion of the residues have the -'unnatural" and rare ^-configuration. 

 Whatever their similarities, the basic peptide, tyrocidine, is essentially 

 inert against bacteria in vivo, while the neutral peptide, gramicidin, is 

 moderately successful in eliminating certain localized infections. This 

 contrast in activity between apparently similar substances suggested 

 that a study of their mode of action might reveal some significant 

 principles. 



It was soon learned that, in the test tube, tyrocidine is in some 

 ways more potent than the other substance; small amounts kill bacteria 

 of many different species, while gramicidin affects only Gram-positive 

 bacteria, principally by inhibiting their growth rather than by killing 

 them. But tyi'ocidine, like many other potent antiseptics, is too un- 

 specific in its reactions to be effective in vivo. It can be demonstrated 

 to precipitate with certain protein anions, and in the presence of pro- 

 tein its action upon bacteria is diminished. It seems probable that 

 tyrocidine, by combining with tissue proteins, becomes at once both 

 harmful to the animal host and almost inert toward the infecting 

 parasite. 



Does the milder, more selective, gramicidin also combine with 

 protein, but merely more specifically, so that it combines with, and 

 inhibits, say, some particular enzyme? Neither gramicidin nor tyro- 

 cidine has much effect upon ordinary hydrolytic enzymes, but when 

 they are tested upon the respiratory and fermentative systems of whole 

 bacteria the situation is somewhat different. Tyrocidine added in 

 lethal quantities to resting bacteria promptly depresses the respiration 

 to a small fraction of the original rate. Gramicidin seldom shows 

 direct inhibitory action; indeed, when environmental conditions are 

 favorable, this agent commonly stimulates susceptible bacteria to 

 respire at two or three times the normal rate. Yet, with staphylo- 

 cocci, the final end products, acetic acid and carbon dioxide, are pro- 

 duced in the same proportion and eventual yield whether or not 

 gramicidin is present. However, the bacteria are not interested in 

 preparing acetic acid (it may even accumulate sufficiently to hamper 

 their activity sometimes) or carbon dioxide as such: as far as we know 

 today their best reasons for oxidizing glucose are (a) to liberate its 

 energy into useful form and (b) to produce intermediates like pyruvic 

 acid, which instead of being further oxidized may serve as raw mate- 



