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Development of non-natural flavanones as antimicrobial agents.

Fowler ZL, Shah K, Panepinto JC, Jacobs A, Koffas MA - PLoS ONE (2011)

Bottom Line: Recently, the use of new treatments containing multiple active ingredients has been shown to increase the effectiveness of existing molecules for some infections, often with these added compounds enabling the transport of a toxic molecule into the infecting species.Flavonoids are among the most abundant plant secondary metabolites and have been shown to have natural abilities as microbial deterrents and anti-infection agents in plants.Of those screened, we identified the synthetic molecule 4-chloro-flavanone as the most potent antimicrobial compound with a MIC value of 70 µg/mL in E. coli when combined with the inhibitor Phe-Arg-ß-naphthylamide, and MICs of 30 µg/mL in S. cerevesiae and 30 µg/mL in C. neoformans when used alone.

View Article: PubMed Central - PubMed

Affiliation: Praxair, Inc. BioPharma Research and Development, Burr Ridge, Illinois, United States of America.

ABSTRACT
With growing concerns over multidrug resistance microorganisms, particularly strains of bacteria and fungi, evolving to become resistant to the antimicrobial agents used against them, the identification of new molecular targets becomes paramount for novel treatment options. Recently, the use of new treatments containing multiple active ingredients has been shown to increase the effectiveness of existing molecules for some infections, often with these added compounds enabling the transport of a toxic molecule into the infecting species. Flavonoids are among the most abundant plant secondary metabolites and have been shown to have natural abilities as microbial deterrents and anti-infection agents in plants. Combining these ideas we first sought to investigate the potency of natural flavonoids in the presence of efflux pump inhibitors to limit Escherichia coli growth. Then we used the natural flavonoid scaffold to synthesize non-natural flavanone molecules and further evaluate their antimicrobial efficacy on Escherichia coli, Bacillus subtilis and the fungal pathogens Cryptococcus neoformans and Aspergillus fumigatus. Of those screened, we identified the synthetic molecule 4-chloro-flavanone as the most potent antimicrobial compound with a MIC value of 70 µg/mL in E. coli when combined with the inhibitor Phe-Arg-ß-naphthylamide, and MICs of 30 µg/mL in S. cerevesiae and 30 µg/mL in C. neoformans when used alone. Through this study we have demonstrated that combinatorial synthesis of non-natural flavonones can identify novel antimicrobial agents with activity against bacteria and fungi but with minimal toxicity to human cells.

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Related in: MedlinePlus

Flavanone chemical structure.Non-natural flavanone structures have functional groups attached to the B-ring in either the 4- (R1) or 3- (R2) position.
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pone-0025681-g001: Flavanone chemical structure.Non-natural flavanone structures have functional groups attached to the B-ring in either the 4- (R1) or 3- (R2) position.

Mentions: Benzaldehyde starting molecules were purchased from Sigma Aldrich and Alfa Aesar. silica gel and sand were ordered from Sigma Aldrich while the organic solvents were purchased from EMD Biosciences. Chemical synthesis of synthetic flavanones has been previously performed [25], [26] and recently reviewed [27]. Briefly, the first steps include the production of a purified and protected acetophenone from the 2,4,6-trihydroxy acetophenone monohydrate. Following de-protection, acetophenone is combined through a Claisen-Schmidt condensation with a slight access of a benzaldehyde containing a substitution of interest to be displayed in the B-ring. This results in the formation of the pre-flavonoid intermediate chalcone, which is then purified and de-protected overnight in HCl and methanol. A pH adjustment is then used to carryout the ring closure to synthesize the final flavanone molecule with the B-ring substitution. Solvent evaporation is then used to obtain crystals of desired flavanone molecule to be purified by flash chromatography. Verification of flavonoids was done using HPLC having retention times between 12 and 17 minutes using a solvent system and C18 column previously described [28]. The flavanone structure is shown in Figure 1 with functional groups attached to the B-ring in either the 4- (R1) or 3- (R2) position.


Development of non-natural flavanones as antimicrobial agents.

Fowler ZL, Shah K, Panepinto JC, Jacobs A, Koffas MA - PLoS ONE (2011)

Flavanone chemical structure.Non-natural flavanone structures have functional groups attached to the B-ring in either the 4- (R1) or 3- (R2) position.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198455&req=5

pone-0025681-g001: Flavanone chemical structure.Non-natural flavanone structures have functional groups attached to the B-ring in either the 4- (R1) or 3- (R2) position.
Mentions: Benzaldehyde starting molecules were purchased from Sigma Aldrich and Alfa Aesar. silica gel and sand were ordered from Sigma Aldrich while the organic solvents were purchased from EMD Biosciences. Chemical synthesis of synthetic flavanones has been previously performed [25], [26] and recently reviewed [27]. Briefly, the first steps include the production of a purified and protected acetophenone from the 2,4,6-trihydroxy acetophenone monohydrate. Following de-protection, acetophenone is combined through a Claisen-Schmidt condensation with a slight access of a benzaldehyde containing a substitution of interest to be displayed in the B-ring. This results in the formation of the pre-flavonoid intermediate chalcone, which is then purified and de-protected overnight in HCl and methanol. A pH adjustment is then used to carryout the ring closure to synthesize the final flavanone molecule with the B-ring substitution. Solvent evaporation is then used to obtain crystals of desired flavanone molecule to be purified by flash chromatography. Verification of flavonoids was done using HPLC having retention times between 12 and 17 minutes using a solvent system and C18 column previously described [28]. The flavanone structure is shown in Figure 1 with functional groups attached to the B-ring in either the 4- (R1) or 3- (R2) position.

Bottom Line: Recently, the use of new treatments containing multiple active ingredients has been shown to increase the effectiveness of existing molecules for some infections, often with these added compounds enabling the transport of a toxic molecule into the infecting species.Flavonoids are among the most abundant plant secondary metabolites and have been shown to have natural abilities as microbial deterrents and anti-infection agents in plants.Of those screened, we identified the synthetic molecule 4-chloro-flavanone as the most potent antimicrobial compound with a MIC value of 70 µg/mL in E. coli when combined with the inhibitor Phe-Arg-ß-naphthylamide, and MICs of 30 µg/mL in S. cerevesiae and 30 µg/mL in C. neoformans when used alone.

View Article: PubMed Central - PubMed

Affiliation: Praxair, Inc. BioPharma Research and Development, Burr Ridge, Illinois, United States of America.

ABSTRACT
With growing concerns over multidrug resistance microorganisms, particularly strains of bacteria and fungi, evolving to become resistant to the antimicrobial agents used against them, the identification of new molecular targets becomes paramount for novel treatment options. Recently, the use of new treatments containing multiple active ingredients has been shown to increase the effectiveness of existing molecules for some infections, often with these added compounds enabling the transport of a toxic molecule into the infecting species. Flavonoids are among the most abundant plant secondary metabolites and have been shown to have natural abilities as microbial deterrents and anti-infection agents in plants. Combining these ideas we first sought to investigate the potency of natural flavonoids in the presence of efflux pump inhibitors to limit Escherichia coli growth. Then we used the natural flavonoid scaffold to synthesize non-natural flavanone molecules and further evaluate their antimicrobial efficacy on Escherichia coli, Bacillus subtilis and the fungal pathogens Cryptococcus neoformans and Aspergillus fumigatus. Of those screened, we identified the synthetic molecule 4-chloro-flavanone as the most potent antimicrobial compound with a MIC value of 70 µg/mL in E. coli when combined with the inhibitor Phe-Arg-ß-naphthylamide, and MICs of 30 µg/mL in S. cerevesiae and 30 µg/mL in C. neoformans when used alone. Through this study we have demonstrated that combinatorial synthesis of non-natural flavonones can identify novel antimicrobial agents with activity against bacteria and fungi but with minimal toxicity to human cells.

Show MeSH
Related in: MedlinePlus