ANTIBACTERIAL ACTION 231 



and streptococci. When injected intravenously, however, it is almost 

 completely inactive against systemic infection. . 



It was demonstrated by tissue culture technique (412) that the he- 

 molytic effect of tyrothricin was due to the presence of gramicidin. 

 When tyrothricin or gramicidin was heated in an aqueous suspension 

 there was a loss of hemolytic and bactericidal activity. Tyrocidine, 

 which is not very hemolytic, showed no marked toxic effect upon the 

 leucocytic elements of the human blood in amounts up to 100 mg. per 

 milliliter for 8 hours. Other investigators (757) have reported that the 

 hemolytic activity of tyrothricin is inherent rather in the tyrocidine 

 fraction, although gramicidin also exhibits a definite hemolytic action. 

 The addition of glucose causes only slight inhibition of the hemolytic 

 effect. 



Treatment with formaldehyde results in the lowering of the hemo- 

 lytic and toxic activity of gramicidin, without reduction of antibacterial 

 properties J this was interpreted as signifying that these properties do 

 not necessarily depend upon the same molecular configuration (S^S)- 



Gramicidin was found to be effective, in amounts as low as i mg., 

 upon a billion gram-positive organisms, whereas tyrocidine acted in 25 

 to 50 times that concentration in the absence of inhibitors (449, 450). 

 Tyrocidine appeared to block all the oxidative systems of the bacteria 

 studied, whereas gramicidin seemed to affect only certain individual 

 reactions. 



Tyrothricin was reported (67) to inhibit enzymatic dehydrogenation 

 not only of glucose but also of a number of other compounds, such as 

 lactic acid, fumaric acid, and glutamic acid. Inhibition of dehydrogenase 

 was parallel to inhibition of growth. 



Both substances were found to exert a protective antibacterial action 

 in mice infected intraperitoneally with susceptible bacteria j gramicidin 

 protected the animals at a level one-fiftieth as high as that required for 

 tyrocidine. Both substances are toxic to animals when injected into the 

 blood stream j they show little toxicity when applied locally by the sub- 

 cutaneous, the intramuscular, or the intrapleural route j oral adminis- 

 tr^ition is not accompanied by toxic effects, but such treatment is in- 

 effective (758). 



Gramicidin remains active in the blood stream, but it has only weak 



