Inhibition of cytochrome systems of heart muscle and certain bacteria by the antagonists of dihydrostreptomycin: 2-alkyl-4-hydroxyquinoline N-oxides

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Abstract
2-Alkyl-4-hydroxyquinoline N-oxides antagonized the inhibitory activity of dihydrostreptomycin against Bacillus subtilis and Staphylococcus aureus but not Escherichia coli or Proteus vulgaris. This antagonistic activity was affected by the length of the 2-alkyl chain, being maximal with a nonyl side chain. The nitrogen oxide group was essential for activity. 2-n-Heptyl-4-hydroxyquinoline N-oxide (heptyl N-oxide) inhibited heart-muscle succinic-oxidase activity but not cytochrome oxidase of succinic dehydrogenase or reduction of cytochrome b. Oxidation of reduced cytochrome b by cytochrome c in the heart-muscle preparation was inhibited by heptyl N-oxide. The inhibition was strikingly reduced by 2:6-dichloro-phenolindophenol. Heptyl N-oxide inhibited growth of B. subtilis and S. aureus, probably as a result of interference with terminal respiration associated with effects on cytochrome oxidation and reduction com-parable to those found with heart-muscle succinic oxidase. Heptyl N-oxide had no effect on respiration of whole cells of E. coli and P. vulgaris, but inhibited respiration of their cell-free preparations. The failure to inhibit respiration of whole cells is probably due to non-penetration of the cell by heptyl N-oxide. The effect of heptyl N-oxide on oxidation of cytochrome b1 in E. coli and P. vulgaris suggests that these pigments are functionally different from the cytochrome b and b1 of heart muscle and S. aureus. respectively. No qualitative difference was observed in the effects of heptyl N-oxide and antimycin A on the heart-muscle succinic-oxidase system. Antimycin A was, however, inactive against the bacterial-cytochrome systems tested, even in cell-free preparations. The modifications of the quinoline N-oxide molecule which resulted in loss of reduction of dihydro-streptomycin-antagonist activity were accompanied by loss or reduction of the effect on cytochrome electron transport.

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