Antibacterial effects of nitric oxide on uropathogenic Escherichia coli during bladder epithelial cell colonization—a comparison with nitrofurantoin

Vumma, Ravi; Bang, Charlotte Sahlberg; Kruse, Robert L.; Johansson, Kjell; Persson, Katarina

doi:10.1038/ja.2015.112

Cited by 14 publications

(14 citation statements)

References 19 publications

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“…The observed impairment of the DOC-FZ synergy by disruption of genes involved in multiple efflux pumps points to a common mechanism that could affect a wide range of efflux pumps simultaneously, such as proton motive force. It has been suggested that nitrofuran compounds during reductive activation might generate NO which subsequently inhibits the electron transport chain (ETC), diminishing the proton motive force across the cytoplasmic membrane [19,20,27] thereby de-energizing multiple efflux pumps and impairing the expulsion of toxic compounds. NO generation from nitrofurans in bacterial cells is, however, speculative, due to the detection limit of the used methods or rapid conversion of NO into other compounds [19,20].…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that nitrofuran compounds during reductive activation might generate NO which subsequently inhibits the electron transport chain (ETC), diminishing the proton motive force across the cytoplasmic membrane [19,20,27] thereby de-energizing multiple efflux pumps and impairing the expulsion of toxic compounds. NO generation from nitrofurans in bacterial cells is, however, speculative, due to the detection limit of the used methods or rapid conversion of NO into other compounds [19,20]. In the present work, we provide evidence for contribution of NO in the interaction between DOC and FZ via the observation that overexpression of NO-detoxifying enzyme Hmp decreased the synergistic interaction between the two agents.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, it has been proposed that the hydroxylamino derivatives could trigger DNA lesions, disrupt protein structure and arrest RNA and protein biosynthesis [15][16][17][18]. Some reports also suggested that nitric oxide could be generated during the activation process, thus inhibiting the electron transport chain of bacterial cells although clear evidence for that is not available so far [19,20]. It is worth mentioning that nitroreductase-encoding genes are not only commonly present in enterobacteria but also found in other bacterial species such as Staphylococcus aureus, Bacillus subtilis, Vibrio fischeri and parasites (e.g.…”

Section: Introductionmentioning

confidence: 99%

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In vitro synergy between sodium deoxycholate and furazolidone against enterobacteria

Olivera

Spagnuolo

et al. 2020

BMC Microbiol

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Background: Antimicrobial combinations have been proven as a promising approach in the confrontation with multi-drug resistant bacterial pathogens. In the present study, we identify and characterize a synergistic interaction of broad-spectrum nitroreductase-activated prodrugs 5-nitrofurans, with a secondary bile salt, Sodium Deoxycholate (DOC) in growth inhibition and killing of enterobacteria. Results: Using checkerboard assay, we show that combination of nitrofuran furazolidone (FZ) and DOC generates a profound synergistic effect on growth inhibition in several enterobacterial species including Escherichia coli, Salmonella enterica, Citrobacter gillenii and Klebsiella pneumoniae. The Fractional Inhibitory Concentration Index (FICI) for DOC-FZ synergy ranges from 0.125 to 0.35 that remains unchanged in an ampicillin-resistant E. coli strain containing a β-lactamase-producing plasmid. Findings from the time-kill assay further highlight the synergy with respect to bacterial killing in E. coli and Salmonella. We further characterize the mechanism of synergy in E. coli K12, showing that disruption of the tolC or acrA genes that encode components of multidrug efflux pumps causes, respectively, a complete or partial loss, of the DOC-FZ synergy. This finding indicates the key role of TolC-associated efflux pumps in the DOC-FZ synergy. Overexpression of Nitric Oxide-detoxifying enzyme Hmp results in a threefold increase in FICI for DOC-FZ interaction, suggesting a role of nitric oxide in the synergy. We further demonstrate that DOC-FZ synergy is largely independent of NfsA and NfsB, the two major activation enzymes of the nitrofuran prodrugs. Conclusions: This study is to our knowledge the first report of nitrofuran-deoxycholate synergy against Gramnegative bacteria, offering potential applications in antimicrobial therapeutics. The mechanism of DOC-FZ synergy involves FZ-mediated inhibition of TolC-associated efflux pumps that normally remove DOC from bacterial cells. One possible route contributing to that effect is via FZ-mediated nitric oxide production.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vitro synergy between sodium deoxycholate and furazolidone against enterobacteria

Olivera

Spagnuolo

et al. 2020

BMC Microbiol

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“…However, NO generation from nitrofurans in bacterial cells remains to be speculative since the trace of NO has yet to be detected using either biochemical or NO-sensing fluorescence methods, possibly due to the detection limit of the used methods or rapid conversion of NO into other compounds (20, 21). In the present work, we provide evidence for the contribution of NO in the interaction between DOC and FZ via the observation that overexpression of NO-detoxifying enzyme Hmp decreased the synergistic interaction between the two agents.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, it has been proposed that the hydroxylamino derivatives could trigger DNA lesions, disrupt protein structure and arrest RNA and protein biosynthesis (15-19). Some reports also suggested that nitric oxide could be generated during the activation process, thus inhibiting electron transport chain of bacterial cells though clear evidence for that is not available as yet (20, 21).…”

Section: Introductionmentioning

confidence: 99%

In vitro synergy between Sodium Deoxycholate and Furazolidone against Enterobacteria via Inhibition of Multidrug Efflux Pumps

Vvh¹,

Olivera²,

Spagnuolo³

et al. 2019

Preprint

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21Antimicrobial combinations have been proven to be a promising approach in the 22 confrontation with multi-drug resistant bacterial pathogens, owing to enhancement of 23 antibacterial efficacy, deceleration of resistance development rate and mitigation of side 24 effects by lowering the doses of two drugs. In the present study, we report that combination 25 of furazolidone (FZ) and other nitrofurans with a secondary bile salt, Sodium Deoxycholate 26 (DOC), generates a profound synergistic effect on growth inhibition and lethality in 27 enterobacteria, including Escherichia coli, Salmonella, Citrobacter gillenii and Klebsiella 28pneumoniae. Taking E. coli as the model organism to study the mechanism of DOC-FZ 29 synergy, we found that the synergistic effect involves FZ-mediated inhibition of efflux pumps 30 that normally remove DOC from bacterial cells. We further show that the FZ-mediated nitric 31 oxide production contributes to the synergistic effect. This is to our knowledge the first report 32 of nitrofuran-DOC synergy against Gram-negative bacteria. 33

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dinF Elicits Nitric Oxide Signaling Induced by Periplanetasin-4 from American Cockroach in Escherichia coli

2021

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Antibacterial effects of nitric oxide on uropathogenic Escherichia coli during bladder epithelial cell colonization—a comparison with nitrofurantoin

Cited by 14 publications

References 19 publications

In vitro synergy between sodium deoxycholate and furazolidone against enterobacteria

In vitro synergy between sodium deoxycholate and furazolidone against enterobacteria

In vitro synergy between Sodium Deoxycholate and Furazolidone against Enterobacteria via Inhibition of Multidrug Efflux Pumps

dinF Elicits Nitric Oxide Signaling Induced by Periplanetasin-4 from American Cockroach in Escherichia coli

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