Chemical, biochemical and microbiological properties of a brominated nitrovinylfuran with broad-spectrum antibacterial activity

Scholz, Therese; Heyl, Carina L.; Bernardi, Dan; Zimmermann, Stefan; Kattner, Lars; Klein, Christian D.

doi:10.1016/j.bmc.2012.11.018

Bioorganic & Medicinal Chemistry

2013

DOI: 10.1016/j.bmc.2012.11.018

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Chemical, biochemical and microbiological properties of a brominated nitrovinylfuran with broad-spectrum antibacterial activity

Therese Scholz¹,

Carina L. Heyl²,

Dan Bernardi³

et al.

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Cited by 26 publications

(34 citation statements)

References 62 publications

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“…It is an efficient antimicrobial with broad-spectrum activity against Gram-positive and Gram-negative bacteria, yeasts and filamentous fungi234. G1 is currently in medical use in Cuba.…”

mentioning

confidence: 99%

“…Just like other vinylfurans (2-furylethylenes), it is a thiolreactive compound and reacts with functional thiol groups in living cells, including those of vital enzymes48910. The reaction center of vinylfurans in these addition reactions is the electrophilic exocyclic double bond911.…”

mentioning

confidence: 99%

“…The reaction center of vinylfurans in these addition reactions is the electrophilic exocyclic double bond911. For example, G1 has been shown to react with the cysteine residues of MurA, a protein that is crucial to peptidoglycan synthesis and is the target of phosphomycin4. Modification of cysteines is irreversible, supposedly rather nonselective and bactericidal, if it is extensive4.…”

mentioning

confidence: 99%

“…For example, G1 has been shown to react with the cysteine residues of MurA, a protein that is crucial to peptidoglycan synthesis and is the target of phosphomycin4. Modification of cysteines is irreversible, supposedly rather nonselective and bactericidal, if it is extensive4. Due to the thiol reactivity, G1 must be short-lived both in a patient and during the standard tests of antimicrobial activity because such tests are carried out in cysteine-containing complex media.…”

mentioning

confidence: 99%

“…Besides adduct formation, G1 induces oxidation of thiol groups and formation of non-native disulfide bonds in a redox reaction. That leads to formation of a thiol-reactive de-bromo derivative of G1, which possesses antibacterial activity acting by the same mechanism as G14. Furthermore, G1 is unstable in aqueous media even in the lack of thiols4.…”

mentioning

confidence: 99%

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Antibacterial activity of the nitrovinylfuran G1 (Furvina) and its conversion products

Allas

Toom

Selyutina

et al. 2016

Sci Rep

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2-Bromo-5-(2-bromo-2-nitrovinyl)furan (G1 or Furvina) is an antimicrobial with a direct reactivity against thiol groups. It is active against Gram-positive and Gram-negative bacteria, yeasts and filamentous fungi. By reacting with thiol groups it causes direct damage to proteins but, as a result, is very short-living and interconverts into an array of reaction products. Our aim was to characterize thiol reactivity of G1 and its conversion products and establish how much of antimicrobial and cytotoxic effects are due to the primary activity of G1 and how much can be attributed to its reaction products. Stability of G1 in growth media as well as its conversion in the presence of thiols was characterized. The structures of G1 decomposition products were determined using NMR and mass-spectroscopy. Concentration- and time-dependent killing curves showed that G1 is bacteriostatic for Escherichia coli at the concentration of 16 μg/ml and bactericidal at 32 μg/ml. However, G1 is inefficient against non-growing E. coli. Addition of cysteine to medium reduces the antimicrobial potency of G1. Nevertheless, the reaction products of G1 and cysteine enabled prolonged antimicrobial action of the drug. Therefore, the activity of 2-bromo-5-(2-bromo-2-nitrovinyl)furan is a sum of its immediate reactivity and the antibacterial effects of the conversion products.

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“…It is an efficient antimicrobial with broad-spectrum activity against Gram-positive and Gram-negative bacteria, yeasts and filamentous fungi234. G1 is currently in medical use in Cuba.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Antibacterial activity of the nitrovinylfuran G1 (Furvina) and its conversion products

Allas

Toom

Selyutina

et al. 2016

Sci Rep

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Targeting the binding pocket of the fluorophore 8‐anilinonaphthalene‐1‐sulfonic acid in the bacterial enzyme MurA

Fathalla

Engel

Ducho

2023

Archiv der Pharmazie

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Abstract8‐Anilinonaphthalene‐1‐sulfonic acid (ANS) has been extensively used as a fluorescent probe to detect conformational changes of proteins. It has been cocrystallized with several of the proteins it is used to monitor, including the bacterial cell wall synthesis enzyme MurA. MurA catalyzes the first committed step of peptidoglycan biosynthesis, converting UDP‐N‐acetylglucosamine (UDP‐GlcNAc) into enolpyruvyl UDP‐GlcNAc. It has been reported before that ANS binds to MurA from Enterobacter cloacae without inhibiting the enzyme's activity up to a concentration of 1 mM ANS. In this study, we present evidence that ANS inhibits the activity of several isoforms of MurA with IC50 values of 18, 22, and 31 µM against wild‐type Escherichia coli, C115D E. coli, and E. cloacae MurA, respectively. This prompted us to test a larger series of structural analogs of ANS for the inhibition of these MurA enzymes, which led to the discovery of compound 26. This ANS analog showed enhanced inhibition of MurA (WT and C115D MurA from E. coli, and E. cloacae MurA) with IC50 values of 2.7, 10, and 14 µM, respectively. Based on our results, the ANS binding pocket was identified as a novel target site for the development of potential antibiotics.

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Application of SAR methods toward inhibition of bacterial peptidoglycan metabolizing enzymes

Drgan

Novič

2018

Journal of Chemometrics

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Structure activity relationship (SAR) methods are applied for a study of inhibition of peptidoglycan metabolizing enzymes, which could represent new antibacterial targets. In this study, we exploit experimental data of inhibition of Mur A and Mur B enzymes for classification of large set of chemicals. Based on inhibitory potency of compounds and their structures from the literature, we developed classification models for new, potential inhibitors of Mur A and Mur B enzymes. The best model for Mur A has the following performance measures for the validation set: 0.85, 0.75, and 0.80, for sensitivity, specificity, and normalized Matthews correlation coefficient, respectively. The same measures of the best Mur B model are 0.94, 0.75, and 0.86. Such models could represent valuable computational tools for theoretic predictions of compounds' activities against specific targets. Additionally, application of such models, like any other computational tools, significantly reduces time and costs in the early phase of drug design.

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Chemical, biochemical and microbiological properties of a brominated nitrovinylfuran with broad-spectrum antibacterial activity

Cited by 26 publications

References 62 publications

Antibacterial activity of the nitrovinylfuran G1 (Furvina) and its conversion products

Antibacterial activity of the nitrovinylfuran G1 (Furvina) and its conversion products

Targeting the binding pocket of the fluorophore 8‐anilinonaphthalene‐1‐sulfonic acid in the bacterial enzyme MurA

Application of SAR methods toward inhibition of bacterial peptidoglycan metabolizing enzymes

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