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Unravelling the Structural and Molecular Basis Responsible for the Anti-Biofilm Activity of Zosteric Acid.

Cattò C, Dell'Orto S, Villa F, Villa S, Gelain A, Vitali A, Marzano V, Baroni S, Forlani F, Cappitelli F - PLoS ONE (2015)

Bottom Line: Despite its potential, the lack of information concerning the structural and molecular mechanism of action involved in its anti-biofilm activity has limited efforts to generate more potent anti-biofilm strategies.Considerations concerning the relationship between structure and anti-biofilm activity revealed that i) the para-sulfoxy ester group is not needed to exploit the anti-biofilm activity of the molecule, it is the cinnamic acid scaffold that is responsible for anti-biofilm performance; ii) the anti-biofilm activity of ZA derivatives depends on the presence of a carboxylate anion and, consequently, on its hydrogen-donating ability; iii) the conjugated aromatic system is instrumental to the anti-biofilm activities of ZA and its analogues.Using a protein pull-down approach, combined with mass spectrometry, the herein-defined active structure of ZA was matrix-immobilized, and was proved to interact with the E. coli NADH:quinone reductase, WrbA, suggesting a possible role of this protein in the biofilm formation process.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Environmental and Nutritional Sciences, Università degli Studi di Milano, Milano, Italy.

ABSTRACT
The natural compound zosteric acid, or p-(sulfoxy)cinnamic acid (ZA), is proposed as an alternative biocide-free agent suitable for preventive or integrative anti-biofilm approaches. Despite its potential, the lack of information concerning the structural and molecular mechanism of action involved in its anti-biofilm activity has limited efforts to generate more potent anti-biofilm strategies. In this study a 43-member library of small molecules based on ZA scaffold diversity was designed and screened against Escherichia coli to understand the structural requirements necessary for biofilm inhibition at sub-lethal concentrations. Considerations concerning the relationship between structure and anti-biofilm activity revealed that i) the para-sulfoxy ester group is not needed to exploit the anti-biofilm activity of the molecule, it is the cinnamic acid scaffold that is responsible for anti-biofilm performance; ii) the anti-biofilm activity of ZA derivatives depends on the presence of a carboxylate anion and, consequently, on its hydrogen-donating ability; iii) the conjugated aromatic system is instrumental to the anti-biofilm activities of ZA and its analogues. Using a protein pull-down approach, combined with mass spectrometry, the herein-defined active structure of ZA was matrix-immobilized, and was proved to interact with the E. coli NADH:quinone reductase, WrbA, suggesting a possible role of this protein in the biofilm formation process.

No MeSH data available.


Related in: MedlinePlus

Synthetic scheme of compounds 36, 37.Reagents and conditions: i) Lindlar catalyst, H2, pyridine, MeOH, r.t., 16 h; ii) 1N NaOH, EtOH/THF (1:1), r.t., 12 h.
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pone.0131519.g005: Synthetic scheme of compounds 36, 37.Reagents and conditions: i) Lindlar catalyst, H2, pyridine, MeOH, r.t., 16 h; ii) 1N NaOH, EtOH/THF (1:1), r.t., 12 h.

Mentions: Zosteric acid was synthesized as already described in a previous work [16]. The cis isomer 38 was obtained starting from cis 4-hydroxycinnamic acid 32 under microwave irradiation in the presence of sulfur trioxide pyridine complex in acetonitrile (Fig 3). The final product was isolated as sodium salt. Most of the substituted cinnamic acid derivatives were prepared in high yield (> 90%) by the Knoevenagel-Doebner procedure. In detail, compounds 2, 7, 8, 11 and 17 were obtained through a one-pot reaction between the suitable substituted benzaldehyde and malonic acid in refluxing pyridine to induce decarboxylation (Fig 4) [20]. The trans geometries of the ethenyl π-bonds were confirmed by proton-proton coupling constants. Cis cinnamic acid 37 was synthesized from the commercially available ethyl phenylpropiolate. The subsequent hydrogenation of alkyne in the presence of the Lindlar catalyst and pyridine in methanol led to the corresponding cis-alkene 36. Then the ester group was hydrolyzed under alkaline conditions to provide the final compound 37 (Fig 5). Esters of cinnamic acid in cis (33) or in trans configuration (23, 24) were prepared by Fischer esterification of the carboxylic group [21]. The protection of the hydroxyl group as methyl ether in the presence of iodomethane in dry N,N-dimethylformamide provided the compounds 35. The hydrolysis of the ester was performed in alkaline conditions to obtain compound 34 (Fig 3).


Unravelling the Structural and Molecular Basis Responsible for the Anti-Biofilm Activity of Zosteric Acid.

Cattò C, Dell'Orto S, Villa F, Villa S, Gelain A, Vitali A, Marzano V, Baroni S, Forlani F, Cappitelli F - PLoS ONE (2015)

Synthetic scheme of compounds 36, 37.Reagents and conditions: i) Lindlar catalyst, H2, pyridine, MeOH, r.t., 16 h; ii) 1N NaOH, EtOH/THF (1:1), r.t., 12 h.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488431&req=5

pone.0131519.g005: Synthetic scheme of compounds 36, 37.Reagents and conditions: i) Lindlar catalyst, H2, pyridine, MeOH, r.t., 16 h; ii) 1N NaOH, EtOH/THF (1:1), r.t., 12 h.
Mentions: Zosteric acid was synthesized as already described in a previous work [16]. The cis isomer 38 was obtained starting from cis 4-hydroxycinnamic acid 32 under microwave irradiation in the presence of sulfur trioxide pyridine complex in acetonitrile (Fig 3). The final product was isolated as sodium salt. Most of the substituted cinnamic acid derivatives were prepared in high yield (> 90%) by the Knoevenagel-Doebner procedure. In detail, compounds 2, 7, 8, 11 and 17 were obtained through a one-pot reaction between the suitable substituted benzaldehyde and malonic acid in refluxing pyridine to induce decarboxylation (Fig 4) [20]. The trans geometries of the ethenyl π-bonds were confirmed by proton-proton coupling constants. Cis cinnamic acid 37 was synthesized from the commercially available ethyl phenylpropiolate. The subsequent hydrogenation of alkyne in the presence of the Lindlar catalyst and pyridine in methanol led to the corresponding cis-alkene 36. Then the ester group was hydrolyzed under alkaline conditions to provide the final compound 37 (Fig 5). Esters of cinnamic acid in cis (33) or in trans configuration (23, 24) were prepared by Fischer esterification of the carboxylic group [21]. The protection of the hydroxyl group as methyl ether in the presence of iodomethane in dry N,N-dimethylformamide provided the compounds 35. The hydrolysis of the ester was performed in alkaline conditions to obtain compound 34 (Fig 3).

Bottom Line: Despite its potential, the lack of information concerning the structural and molecular mechanism of action involved in its anti-biofilm activity has limited efforts to generate more potent anti-biofilm strategies.Considerations concerning the relationship between structure and anti-biofilm activity revealed that i) the para-sulfoxy ester group is not needed to exploit the anti-biofilm activity of the molecule, it is the cinnamic acid scaffold that is responsible for anti-biofilm performance; ii) the anti-biofilm activity of ZA derivatives depends on the presence of a carboxylate anion and, consequently, on its hydrogen-donating ability; iii) the conjugated aromatic system is instrumental to the anti-biofilm activities of ZA and its analogues.Using a protein pull-down approach, combined with mass spectrometry, the herein-defined active structure of ZA was matrix-immobilized, and was proved to interact with the E. coli NADH:quinone reductase, WrbA, suggesting a possible role of this protein in the biofilm formation process.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Environmental and Nutritional Sciences, Università degli Studi di Milano, Milano, Italy.

ABSTRACT
The natural compound zosteric acid, or p-(sulfoxy)cinnamic acid (ZA), is proposed as an alternative biocide-free agent suitable for preventive or integrative anti-biofilm approaches. Despite its potential, the lack of information concerning the structural and molecular mechanism of action involved in its anti-biofilm activity has limited efforts to generate more potent anti-biofilm strategies. In this study a 43-member library of small molecules based on ZA scaffold diversity was designed and screened against Escherichia coli to understand the structural requirements necessary for biofilm inhibition at sub-lethal concentrations. Considerations concerning the relationship between structure and anti-biofilm activity revealed that i) the para-sulfoxy ester group is not needed to exploit the anti-biofilm activity of the molecule, it is the cinnamic acid scaffold that is responsible for anti-biofilm performance; ii) the anti-biofilm activity of ZA derivatives depends on the presence of a carboxylate anion and, consequently, on its hydrogen-donating ability; iii) the conjugated aromatic system is instrumental to the anti-biofilm activities of ZA and its analogues. Using a protein pull-down approach, combined with mass spectrometry, the herein-defined active structure of ZA was matrix-immobilized, and was proved to interact with the E. coli NADH:quinone reductase, WrbA, suggesting a possible role of this protein in the biofilm formation process.

No MeSH data available.


Related in: MedlinePlus