Paraquat and nitrofurantoin inhibit growth ofescherichia coliby inducing stringency

Abstract

The herbicide paraquat and the antibiotic nitrofurantoin (redox-active compounds that can transfer electrons singly to oxygen) induced intracellular accumulation of the regulatory inhibitor guanosine tetraphosphate (stringency) in Escherichia coli. This mechanism is sufficient to account for the rapid bacteristasis produced in minimal medium by these agents. The growth inhibition and stringency induction were prevented by inclusion of specific amino acids in the medium. Stringency was first reported to result from amino acid starvation, with unloaded transfer ribonucleic acids (tRNAs) acting as the trigger. Previously, inhibition of growth of E. coli by paraquat and hyperbaric oxygen were shown to be prevented by inclusion in the medium of a nearly identical profile of specific amino acids, including branched-chain amino acids, which were required because of poisoning of their biosynthesis at the dihydroxyacid dehydratase site, and stringency has been induced by hyperbaric oxygen poisoning. Thus, stringency induction via a common poisoned site in branched-chain amino acid biosynthesis appears to be a shared mechanism of toxicity for these agents and hyperbaric oxygen, which also share the propensity for one-electron-transfer, free-radical reactions in cells.

Growth inhibition of putrefactive anaerobe 3679 caused by stringent-type response induced by protonophoric activity of sorbic acid

“…Seither and Brown (46) reported that growth inhibition of E. coli by paraquat, a herbicide, and nitrofurantoin, an antibiotic, was induced by the stringent response. Both compounds are believed to block biosynthetic pathways of specific amino acids and cause amino acid starvation in the cells.…”

Hyperoxia and the antimicrobial susceptibility of Escherichia coli and Pseudomonas aeruginosa

“…The stringency response is defined as intracellular accumulation of guanosine 5'-diphosphate 3'-diphosphate, which is a regulatory inhibitor of biosynthetic processes in bacteria (25). Nitrofurantoin blocks synthesis of branchedchain amino acids such as valine and leucine (26). The observed decrease in the MIC of nitrofurantoin for a clinical bacterial isolate (E. coli serotype 018) during hyperoxic exposure may be due to a combination of these mechanisms.…”

“…This oxygen-derived free radical may undergo further reduction to form H202, which is toxic for bacteria. Hydrogen peroxide may take part in the Fenton reaction, where it is converted to the highly reactive hydroxyl radical (16 (25,26). The stringency response is defined as intracellular accumulation of guanosine 5'-diphosphate 3'-diphosphate, which is a regulatory inhibitor of biosynthetic processes in bacteria (25).…”

SB 205952, a novel semisynthetic monic acid analog with at least two modes of action

“…SB 205952 therefore appears to have a second mechanism of action which induces stringency but which is independent of IRS inhibition. Nitrofurantoin and related compounds (27,38) are among the agents known to invoke ppGpp accumulation and stringency, and oxidative inactivation of dihydroxyacid dehydratase has been implicated (38). This enzyme is a key component of the isoleucine biosynthetic pathway in which it functions to convert ␣,␤-dihydroxy-␤-methylvalerate to ␣-keto-␤-methylvalerate (41).…”