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Nitrofurantoin (NF)-resistant mutants of Escherichia coli were isolated as described previously (18). One of the mutants (SSJ-2) was found to possess NF reductase activity equal to that of its parent (E. coli KL16). Two NF-resistant transductional derivatives, SSJ-2A and SSJ-2B, were isolated using SSJ-2 as the donor. SSJ-2 was found to be a double mutant carrying two mutations, nfnA and nfnB, while SSJ-2A (nfnA) and SSJ-2B (nfnB) carried these mutations individually. Heated extracts from SSJ-2A and SSJ-2B were found to inhibit the reduction of NF by unheated extracts of the NF-sensitive strain E. coli KL16 in vitro. Unheated extracts of these mutants reduced NF poorly relative to E. coli KL16. The poor reduction of NF by unheated extracts of SSJ-2A and SSJ-2B was greatly stimulated by heated extracts of SSJ-2B and SSJ-2A, respectively, and also by heated extracts of E. coli KL16. When heated extracts of SSJ-2A and SSJ-2B were mixed in a particular ratio and added to unheated extracts of E. coli KL16 they lost their inhibitory activity. Two proteins, designated inhibitor A and inhibitor B, have been partially purified from heated extracts of SSJ-2B and SSJ-2A, respectively. Their respective molecular weights, as determined by gel chromatography, were 37,000 and 20,500. The two inhibitors bound nitrofurantoin in vitro, and the NF-binding ability was lost when mixed in the molar ration of 3/1 (B/A). These observations were rationalized in terms of a hypothesis which explains (i) maximal NF reduction in wild-type cells, (ii) maximal NF reduction of nfnA-nfnB- double mutant, and (iii) poor NF reduction in nfnA- or nfnB- single mutants. The possible role of these inhibitors in nitrofurantoin resistance is also discussed.
Changes in the biogenesis of corticosteroids caused by nitrofurans were studied. The three nitrofurans used: furazolidone, furaltadone and nitrofurantoin, altered the steroid production/release by porcine adrenocortical cells in vitro during 1 h incubations. With pregnenolone as a substrate the nitrofurans inhibited aldosterone production/release. Although the nitrofurans differed in potency (nitrofurantoin > furazolidone > furaltadone) maximum inhibition occurred at 100 microM. In this concentration the nitrofurans changed also the release/production of other corticosteroids. The output of corticosterone and cortisol decreased by 50%. The production/release of deoxycortisol stayed the same. In contrast the output of progesterone and 17alpha-hydroxyprogesterone increased to more than 200% of control. The nitrofurans slightly reduced the output of androstenedione. No significant increases of the production/release of other steroids (testosterone, dehydroepiandrosterone, estradiol-17beta and estrone) by the cell suspension could be observed. The profile of the nitrofuran-induced changes lead to the conclusion that nitrofurans interfere with mitochondrial enzymes. These enzymes, presumably cytochrome P450(11,18) mediate the hydroxylation and the oxidation at C11 and C18, the final steps in the biogenesis of aldosterone, corticosterone and cortisol. The rapid and reversible fall in the output of these steroids occurs in vitro at concentrations which are below therapeutic blood concentrations seen in vivo. At higher concentrations the nitrofurans hinder the biogenesis of androgens. Thus nitrofurans can also affect steps in the steroid biogenesis located in the endoplasmatic reticulum.
Anaerobic Tritrichomonas foetus hydrogenosomes supplemented with pyruvate and CoA effectively reduce nitrofurans and metronidazole to their respective anion free radicals. Addition of purified ferredoxins from Clostridium pasteurianum or Spinacia oleracea to these preparations causes a great stimulation of metronidazole reduction, but does not affect nitrofuran reduction. A similar stimulatory effect of ferredoxin on metronidazole reduction, but not on nitrofuran reduction, is observed in incubations containing purified NADPH:ferredoxin oxidoreductase from S. oleracea. NADH is less effective than pyruvate as a reducing cofactor for metronidazole and nitrofuran reduction by the hydrogenosomes, and these activities are not modified by the addition of ferredoxins. In contrast to the results observed with hydrogenosomes, the T. foetus soluble fraction supplemented with NADH or NADPH is able to reduce nitrofurans, but not metronidazole. Under aerobic conditions, the anion free radical metabolites generated from metronidazole and nitrofurans are oxidized, resulting in catalytic superoxide anion formation as detected by spin-trapping experiments. Oxygen consumption and H2O2 formation by T. foetus hydrogenosomes and NADPH:ferredoxin oxidoreductase are also stimulated by nitrofurans and high concentrations of metronidazole. Addition of ferredoxin enhances metronidazole-stimulated, but not nitrofuran-stimulated, oxygen consumption and H2O2 formation in both systems. These results support the role of air oxidation as a detoxification reaction of the metronidazole anion radical and the involvement of ferredoxin in its formation. On the other hand, redox cycling of nitrofurans with formation of high steady state concentrations of oxygen-derived radicals might be of toxicological significance.
There have been few recent reviews of the nitrofurans in the literature, and none include recently available data on the use of nitrofurazone (nitrofural) in the prevention of catheter-associated urinary tract infection (CAUTI). Nitrofurazone and nitrofurantoin are the only nitrofurans that have become established in clinical use in the 20th century. These 2 nitrofurans have remained clinically useful against a wide spectrum of gram-positive and gram-negative bacteria, including many strains of common urinary tract pathogens. Today, the primary use of nitrofurantoin is as an oral antibacterial treatment for genitourinary infections. Nitrofurazone is primarily used as a topical antibacterial agent in burns and skin grafts and recently was approved for the prophylaxis of CAUTI. The recent development of a nitrofurazone-impregnated catheter as a novel modality in the prevention of CAUTI reflects a renewed interest in the effectiveness of nitrofurans. In an era when concern about bacterial resistance to many anti-infective agents is growing, the nitrofurans have continued to be active against organisms that have developed resistance to antibacterials. The presence of multiple mechanisms of action for the nitrofurans might be expected to reduce the ability of bacteria to develop resistance. Considering that an emergence of resistance to the nitrofurans has not appreciably occurred after several decades of clinical use, the nitrofurans may be unique among common antibacterial agents in this regard.
In order to elucidate the mechanism of the biological activation of nitrofurans, the interaction of these compounds with lipoamide dehydrogenase (LipDH)** was investigated. LipDH catalysed one-electron reduction of several nitrofuran derivatives. The reaction could be demonstrated spectroscopically and was enhanced by cadmium, arsenite and anaerobiosis. The role of flavin in the nitroreductase activity was supported by (a) the nitrofuran effect on the spectral properties of anaerobic, arsenite-inhibited, NADH-reduced LipDH; (b) FAD catalytic activity in a NADH-nitrofuran model system; and (c) the nitroreductase activity of LipDH monomer. Two-electron nitrofuran reduction to less oxidized products was inhibited by cadmium, arsenite and NAD+. The possible role of reactive nitrosofuran derivatives as intermediates of the nitrofuran reduction sequence was supported by the LipDH capability for catalysing 2-nitroso-1-naphthol redox-cycling. The nitroso naphthol reduction was inhibited by cadmium and arsenite, like the two-electron nitrofuran reduction.
A group of nitrofurans (5-nitro-2-furaldehyde, nifuroxime, nitrofurazone, nitrofurantoin, 5-nitro-2-furoic acid and 2-nitrofuran) were evaluated for inhibition of mitogenesis (DNA synthesis) in human peripheral blood T cells. T cells, either triggered by phorbol myristate acetate (PMA) or in the presence of accessory cells, were activated with a specified mitogen [phytohemagglutin (PHA), concanavalin A (ConA), or anti-CD3] and the amount of tritiated thymidine incorporated into DNA was determined. The results obtained indicate that nitrofurans inhibit mitogenesis irrespective of activator. 5-Nitro-2-furaldehyde was much more inhibitory than the other compounds, while 2-nitrofuran was less inhibitory. When the aldehyde group (5-nitro-2-furaldehyde) was replaced by a carboxyl group (5-nitro-2-furoic acid), the inhibitory activity was also reduced greatly. These results show that while the nitro group alone confers inhibitory activity to the furan ring, the group at the 2 position is crucial. In general, the mitogenic response of purified T cells (lacking accessory cells) triggered by PMA (phorbol ester) was inhibited less than that of the T cell-accessory cell system. With the latter, 50% inhibition of T cell mitogenesis was achieved by nifuroxime, nitrofurazone, and nitrofurantoin at 45-51 and 34-39 microM with PHA and ConA respectively. When purified T cells were used, the values were 71-85 and 55-60 microM respectively. For a given drug concentration, mitogenesis was more inhibited when induced by ConA or anti-CD3 than by PHA. The importance of using a single cell system (purified T cells) was emphasized by the interesting finding that only this system showed enhancement of mitogenesis, up to 35-40% at low drug levels. With the exception of the nitrofuraldehyde, the nitrofurans at strongly inhibitory levels were only moderately cytotoxic, exhibiting 62-85% cell survival after exposure to drug for 68 hr. Our results suggest that nitrofurans inhibit T cell mitogenesis by a relatively non-toxic mechanism; these results are comparable to those obtained for mammalian cells under aerobic conditions.
The use of nitrofuran antibiotics in food-producing animals is prohibited within the EU. Countries in the EU, as well those intending to export food to the EU, must ensure that their products are free from nitrofuran residues. As a result of recent global problems where chicken meat from a wide range of countries has been contaminated with nitrofuran metabolites, an investigation was performed to discover whether or not residues of the nitrofurans might be transferred from parent breeder chickens to their offspring broilers. Four groups of broiler breeders were each treated with one of the nitrofurans: furazolidone, nitrofurazone, nitrofurantoin or furaltadone. Residues of their side-chain metabolites, AOZ, SEM, AHD and AMOZ, were detected in the fertilised eggs at concentrations up to 1567 microg/kg. However, in the chicks that subsequently hatched from these eggs, residue concentrations of SEM, for example, were only found up to 26.6 and 32.5 microg/kg in liver and muscle, respectively, for 1-d-old chicks. Residue concentrations in tissues had fallen below the detection limit of the analytical method for 40-d-old broiler chicks, for all compounds except for semicarbazide (SEM, the nitrofurazone metabolite). Relatively high concentrations of nitrofurans are available to the newly hatched chick through the egg yolk. However, most of these residues are neither utilised nor deposited in the liver or muscle.
Nitrofuran AF-2 displayed greater inhibitory effect than did nitrofuran Z when a mixed bacterial culture, including several proteolytic bacteria, isolated from shrimp was subjected to these compounds in vitro. Nitrofuran Z exhibited greater bactericidal properties than did chlortetracycline in all cultures used. Only 10 mug of nitrofuran AF-2 per ml was sufficient to inhibit the growth of mixed bacteria in nutrient broth, whereas 50 mug of nitrofuran Z per ml was necessary to accomplish the same inhibition. A 50-mug amount of chlortetracycline per ml displayed about the same inhibitory effect as either 10 mug of AF-2 per ml or 20 mug of Z per ml. The isolated proteolytic bacteria showed greater suppression of growth when subjected to AF-2 than when subjected to Z; however, both nitrofurans were effective in preventing growth. The addition of either 1 mug of AF-2 per ml or 5 mug of Z per ml to nutrient broth inhibited the growth of Achromobacter aquarmarinus, whereas chlortetracycline was less effective, requiring about 20 mug to suppress growth to the same degree.
Earlier studies showed a strong carcinogenicity of the nitrofuran compound 1,2-dihydro-2-(5'nitro-2'furyl)-3-hydroxy-quinazoline-4-one since carcinomas of the urinary bladder in rats and dogs appeared already after six months of treatment. In order to compare possible mutagenic properties of the compound and to get some information on the genotoxic moiety of the molecule, the genotoxicity of four nitrofuran derivatives and of two chemical analogues without the nitrofuran residue was tested in the Ames Test, E. coli WP2 uvrA, and in the rec-assay with Bacillus subtilis. 2-Nitrofuran was also included in this study. Only 2-nitrofuran and the nitrofuran containing derivatives were active in these bacterial test systems. Metabolic activation by liver homogenate was not needed to demonstrate the genotoxic effects. 1,2-dihydro-2-(5'nitro-2'furyl)-3-hydroxy-quinazoline-4-one was more active in the mutagenicity tests in the presence of exogenous metabolic activation. Further studies revealed that this compound was able to induce unscheduled DNA synthesis but was not mutagenic in the micronucleus test.
Heart lipoamide dehydrogenase (LADH) catalyzed redox-cycling and O2-. production by (5-nitro-2-furfurylidene)amino derivatives using NADH as electron donor. NADH was a much more effective electron donor than NADPH for the nitroreductase activity. O2-. production was demonstrated by cytochrome c reduction, adrenochrome formation and the effect of superoxide dismutase. Under optimum conditions, nitroreductase activity was about 1% of LADH activity. One electron oxygen reduction and NADH oxidation correlated in 2:1 stoichiometry. The nitroreductase kinetics was in accordance with an ordered bi-bi mechanism. Nitrofuran derivatives bearing unsaturated five- or six-membered nitrogen heterocycles were more effective substrates than those bearing other groups, namely nifurtimox, nitrofurazone, nitrofurantoin and 5-nitro-2-furoic acid. Other nitro compounds (chloramphenicol, benznidazole, 2-nitroimidazole and 5-nitroindole) were ineffective. With the triazole, traizine and imidazole nitrofuran derivatives, the nitroreductase pH curve showed a maximum at pH 8.8, different from the pH optimum for the lipoamide reductase and diaphorase activities. Spectroscopic observations demonstrated pH-dependent structural changes in the triazole(I) and triazine derivatives which would affect their behavior as nitroreductase substrates. The nitroreductase activity was inhibited by p-chloromercuribenzoate and enhanced by cadmium and arsenite, whereas the NADH-induced LADH inactivation failed to affect the nitroreductase activity. In the absence of oxygen. LADH catalyzed nitrofuran reduction to products more reduced than the nitroanion, which were not reoxidized by oxygen. The anaerobic nitrofuran reduction was inhibited by cadmium and arsenite. The assayed nitrofuran compounds did not inhibit LADH lipoamide reductase activity, at variance with their action on glutathione reductase (Grinblat et al., Biochem Pharmacol 38: 767-772, 1989).
Nitrofuran derivatives are a class of compounds which exhibit mutagenic and cytotoxic effects in bacteria and mammalian cells in tissue culture after metabolic activation by endogenous nitroreductases. The relationship between mutation and induction of pleiotropic error-prone repair functions (the 'SOS' system) in bacteria following exposure to nitrofurans was examined. A variety of nitrofurans were found to induce protein X, the recA+ protein, which is characteristic of error-prone repair. Furthermore, induction of the 'SOS' system depended on reductive activation of the mutagen. The use of a mutant thermally inducible for error-prone repair functions (tif-1) provided direct examination of bacteria exposed to non-lethal doses of nitrofuran. These results distinguish between mutants which arose from directly induced base mispairing and those which occur only after induction of error-prone repair functions. The mutational activity of AF2 (furylfuramide) was almost entirely dependent on the induction of error-prone repair since very few tryptophan revertants were detected in conditions which did not induced the 'SOS' repair system. We present a model for mutation induction by nitrofurans in bacteria.