Action of some nitrofuran derivatives on glucose metabolism, ATP levels, and macromolecule synthesis in Escherichia coli

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Abstract
In Escherichia coli B/r, nitrofurazone (NF; semicarbazone of 5-nitro-2-furaldehyde) at a concentration of 25 μg/ml inhibited nucleic acid synthesis as judged both by chemical analysis and by incorporation of [3H]thymidine and [3H]uracil into acid-insoluble material. This concentration of NF somewhat inhibited glucose and pyruvate oxidation and reduced the ATP levels in treated bacteria. A lower concentration (5 μg/ml), however, increased the ATP levels and stimulated the incorporation of [3H]uracil into acid-insoluble material. AF2 (2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide) at 2.5 μg/ml (a concentration which inhibits [3H]thymidine incorporation to about the same extent as 25 μg/ml NF) inhibited net accumulation of both RNA and DNA but stimulated the incorporation of [3H]uracil. Treatment with AF2 also increased the ATP levels which in turn increased the conversion of [3H]uracil to UTP. AF2 somewhat inhibited the oxidation of glucose and pyruvate to CO2. Nitrofurantoin (25 μg/ml) and furazolidone (15 μg/ml) gave results similar to those with nitrofurazone, while N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) at 5 μg/ml was similar in its action to AF2. There was no direct correlation between inhibition of glucose oxidation or nucleic acid synthesis and killing.In strain NFR 207, a mutant which lacks the O2-insensitive nitrofuran-reductase I and is therefore unable to 'activate' nitrofurans, AF2 up to a concentration of at least 10 μg/ml had essentially no effect on glucose metabolism, ATP levels, incorporation of uracil and thymidine, or accumulation of RNA or DNA. In contrast, nitrofurazone produced effects in NFR 207 which were qualitatively similar to those in B/r but somewhat less extensive. These results indicate that all of the inhibitory effects of AF2 may be due to its metabolites while some of the effects of nitrofurazone are mediated by the unmetabolized drug.