Nitrofuran mutagenicity: induction of frameshift mutations

Obaseiki-Ebor, Emmanuel E.; Akerele, John O.

doi:10.1016/0165-7992(86)90114-4

Cited by 11 publications

(9 citation statements)

References 21 publications

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“…These findings are in agreement with other investigations (Chatterjee and Ghosh 1979) that demonstrate significant filamentation of V. cholerae cells resulting from the inhibition of cell division. In attempting to explain the basis of mutation caused by Nf in E. coli cells (Obaseiki‐Ebor and Akerele 1986; Mukherjee et al. 1990), it was demonstrated that the agent inhibited cell division and produced interstrand cross‐links in V. cholerae and E. coli DNA.…”

Section: Discussionmentioning

confidence: 99%

In vitro activity of nitrofuran derivatives on growth and morphology of Salmonella enterica serotype Enteritidis

Chadfield¹,

Hinton

2004

J Appl Microbiol

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Aims:To evaluate the effect of nitrofuran derivatives furazolidone (Fz) and nitrofurantoin (Nf) on Salmonella enterica serovar Enteritidis PT4 in vitro, with regard to cell growth, morphology and ultrastructure. Methods and Results: The effects of Fz on the growth rates of Fz resistant (Fz R ) and sensitive (Fz S ) strains were assessed by viable counts. Over 24 h incubation, concentrations of <1 lg ml )1 of Fz were bacteriostatic to the Fz S strain. The Fz R strain tolerated concentrations up to 16 lg ml )1 before cell numbers diminished over the same time period. The effect on the growth rate of the Fz S strain after 1 h exposure to supra-inhibitory concentrations of Fz, gave a maximum response at 32X minimum inhibitory concentration (MIC) of 4AE5 h. Effects on the ultrastructure of bacterial cells by scanning electron and transmission microscopy, and DNA-specific staining with DAPI of the Fz S strain exposed to nitrofurans were studied. Abnormalities such as extensive filamentation with sparse, sporadic nucleotide distribution and evidence of extrusions in the cell envelope in the form of blebs were evident. Conclusions: Nitrofurans exert their bactericidal effect on Salmonella by inducing extensive structural alteration after exposure at sub-or suprainhibitory concentrations, involving inhibition of cell division because of the activated drug causing an intercalating type of binding in DNA. Significance and Impact of the Study: These results demonstrate the in vitro activity of the nitrofuran derivatives, furazolidone and nitrofurantoin on Salmonella, defining the pharmacodynamics and physical nature of their action as therapeutic agents.

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Section: Discussionmentioning

confidence: 99%

In vitro activity of nitrofuran derivatives on growth and morphology of Salmonella enterica serotype Enteritidis

Chadfield¹,

Hinton

2004

J Appl Microbiol

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“…One such example of 'old' drugs are 5-nitrofurans, a broadspectrum class of antibacterials. Although they have had a controversial past due to their mutagenicity and carcinogenicity [4,5], they remain effective, have low prevalence of resistance [6][7][8][9][10] and are still clinically used today. The OPEN ACCESS 5-nitrofuran class of antibacterials includes commercially available furazolidone (FZ), nitrofurantoin (NIT) and nitrofurazone (NFZ).…”

Section: Introductionmentioning

confidence: 99%

“…Although they have had a controversial past due to their mutagenicity and carcinogenicity [4,5], they remain effective, have low prevalence of resistance [6][7][8][9][10] and are still clinically used today. The OPEN ACCESS 5-nitrofuran class of antibacterials includes commercially available furazolidone (FZ), nitrofurantoin (NIT) and nitrofurazone (NFZ). FZ is used to treat diarrhoea and as a component of combination therapy against Helicobacter pylori, NIT to treat urinary tract infections, and NFZ as a topical treatment for burns and wounds [11].…”

Section: Introductionmentioning

confidence: 99%

In vitro synergy of 5-nitrofurans, vancomycin and sodium deoxycholate against Gram-negative pathogens

Olivera

Davenport

et al. 2021

Journal of Medical Microbiology

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Introduction. There is an urgent need for effective therapies against bacterial infections, especially those caused by antibiotic-resistant Gram-negative pathogens. Hypothesis. Synergistic combinations of existing antimicrobials show promise due to their enhanced efficacies and reduced dosages which can mitigate adverse effects, and therefore can be used as potential antibacterial therapy. Aim. In this study, we sought to characterize the in vitro interaction of 5-nitrofurans, vancomycin and sodium deoxycholate (NVD) against pathogenic bacteria. Methodology. The synergy of the NVD combination was investigated in terms of growth inhibition and bacterial killing using checkerboard and time-kill assays, respectively. Results. Using a three-dimensional checkerboard assay, we showed that 5-nitrofurans, sodium deoxycholate and vancomycin interact synergistically in the growth inhibition of 15 out of 20 Gram-negative strains tested, including clinically significant pathogens such as carbapenemase-producing Escherichia coli , Klebsiella pneumoniae and Acinetobacter baumannii , and interact indifferently against the Gram-positive strains tested. The time-kill assay further confirmed that the triple combination was bactericidal in a synergistic manner. Conclusion. This study demonstrates the synergistic effect of 5-nitrofurans, sodium deoxycholate and vancomycin against Gram-negative pathogens and highlights the potential of the combination as a treatment for Gram-negative and Gram-positive infections.

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“…Nitrofurans and DOC have variable effects on Gram-negative bacteria, but their exact mechanisms of action are not fully understood. Nitrofurans are prodrugs (10) whose reactive intermediates were reported to damage DNA, induce oxidative stress, and inhibit translation (11)(12)(13)(14). On the other hand, the effects of DOC include DNA damage, oxidative stress, protein aggregation, and membrane damage (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Correlated transcriptional responses provide insights into the synergy mechanisms of the furazolidone, vancomycin and sodium deoxycholate triple combination in Escherichia coli

Olivera¹,

Cox

Rowlands³

et al. 2021

Preprint

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Effective therapeutic options are urgently needed to tackle antibiotic resistance. Furazolidone (FZ), vancomycin (VAN), and sodium deoxycholate (DOC) show promise as their combination can synergistically inhibit the growth of, and kill, multidrug-resistant Gram-negative bacteria that are classified as critical priority by the World Health Organization. Here, we investigated the mechanisms of action and synergy of this drug combination using a transcriptomics approach in the model bacterium Escherichia coli. We show that FZ and DOC elicit highly similar gene perturbations indicative of iron starvation, decreased respiration and metabolism, and translational stress. In contrast, VAN induced envelope stress responses, in agreement with its known role in peptidoglycan synthesis inhibition. FZ induced the SOS response consistent with its DNA damaging effects, but we demonstrate that using FZ in combination with the other two compounds enables use of lower dosages and largely mitigates its mutagenic effects. Based on the gene expression changes identified, we propose a synergy mechanism where the combined effects of FZ, VAN, and DOC amplify damage to Gram-negative bacteria while simultaneously suppressing antibiotic resistance mechanisms.

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Nitrofuran mutagenicity: induction of frameshift mutations

Cited by 11 publications

References 21 publications

In vitro activity of nitrofuran derivatives on growth and morphology of Salmonella enterica serotype Enteritidis

In vitro activity of nitrofuran derivatives on growth and morphology of Salmonella enterica serotype Enteritidis

In vitro synergy of 5-nitrofurans, vancomycin and sodium deoxycholate against Gram-negative pathogens

Correlated transcriptional responses provide insights into the synergy mechanisms of the furazolidone, vancomycin and sodium deoxycholate triple combination in Escherichia coli

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