MODES OF ACTION OF ANTIBIOTICS 



93 



also l)eeii suggested (Wasserman, 1053). 

 Zeller (1953) observed an inhibition of 

 diamine oxidase in mycobacteria and as- 

 cribed this to the digiianidine residue of the 

 antibiotic. 



According to Geiger (1947), the increased 

 ability of E. coli cells, first permitted to act 

 on fumarate or other carbon compounds, 

 to oxidize amino acids is nullified by strepto- 

 mycin. Yoshida and Sevag (1958) suggested 

 that streptomycin interferes with the incor- 

 poration of phosphate by E. coli cells. The 

 mechanism of action of streptomycin on 

 bacteria was described by Linz (1948) as 

 consisting first of the absorption of strepto- 

 mycin by the bacterial cells, later followed 

 by the action of the antibiotic on the essen- 

 tial SH groups concentrated in enzymatic 

 complexes. 



Lightbown (1954) reported that Pseudo- 

 monas aeruginosa produced a highly acti\-e 

 antagonist of streptomycin and dihydro- 

 streptomj^cin activity. The antagonist has 

 been identified as a mixture of 4-hydroxy- 

 quinoline-N-oxides with alkyl chains of 

 seven, eight, and nine carbons. It inhibits 

 respiration via the cytochrome system 

 (Lightbown and Jackson, 1956). Hancock 

 (1960b) measured the uptake of radioactive 

 streptomycin by cells of various bacteria. 

 When growth is inhibited, the radioactivity 

 taken corresponds to 0.06 ng per mg of 

 cells for B. megaterium, 1.5 mS for Staph, 

 aureus, and 1.6 Mg for B. subtilis. The uptake 

 by the first corresponds to about 5 X 10^ 

 molecules of streptomycin per cell. In the 

 case of streptomycin-resistant strains, the 

 uptake is then 1 per cent of this amount. 

 When the growth-inhibitory effect of strep- 

 tomycin (25 ij.g per ml) on B. subtilis is 

 antagonized b}' 2-heptyl-4-hydroxy(iuino- 

 line-X-oxide (0.4 fig per ml), the uptake of 

 radioactivity is only about 25 per cent of 

 that in the absence of the antagonist. Ac- 

 cording to Hancock, "The uptake of strep- 

 tomycin into the cell is associated with 



aerobic respiratory processes and is reduced 

 when these are depressed." 



Umbreit (1949) and Oginsky (1953) sug- 

 gested that streptomycin inhibits terminal 

 oxidation in sensitive organisms by inhibit- 

 ing the condensation of pyruvate and 

 oxalacetate to 2-phospho-4-carboxyadipic 

 acid. This concept has been questioned by 

 Paine and Clark (1954), who reported that 

 a strain of Staph, aureus, which under anaero- 

 bic conditions simply reduced pyruvate to 

 lactate, was readily killed by the antibiotic. 

 It has also been observed that the antibiotic 

 may mhibit, stimulate, or have no effect on 

 oxygen uptake, depending on the carbon 

 source on which the organism was grown. 

 The killing action of streptomycin was cor- 

 related with the metabolic activity of the 

 organism but not with its respiration. The 

 role of streptomycin in the inhibition of 

 synthesis of enzymes responsible for con- 

 tinued oxidation in the cells was also sug- 

 gested. 



Katagiri et al. (1960b) could not demon- 

 strate any inhibiting effect of dihydro- 

 streptomycin on the oxalacetate-pyruvate 

 condensation reaction in E. coli, nor was the 

 anaerobic production of lactate from glucose 

 inhibited. Anaerobic fermentation of P3^ru- 

 vate by cells grown in a casein hydrolysate 

 medium w^as stronglj^ inhibited by dihydro- 

 streptomycin; the inhibiting efTect of dihy- 

 drostreptomycin on the phosphoroclastic 

 split of pyruvate into acetate and formate 

 could also be demonstrated. 



However, although the oxidation of pyru- 

 vate, acetate, and dicarboxylates by washed 

 cells of E. coli was affected only slightly by 

 dihydrostreptomycin or chloramphenicol, 

 the oxidation of these carbon compounds 

 was very sensitive to oxytetracj^cline. Dihy- 

 drostreptomycin showed an accelerating 

 efTect on aerobic decomposition of a-keto- 

 glutarate in the presence of appropriate 

 carbon and nitrogen sources by washed, 

 dried, or dry ice-treated cells of E. coli or 



