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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

Growth-inhibitory activity of 4-Cl-Flavanone (FNN) against C. neoformans.Agar plate spotting in four 10-fold dilutions after cell exposure to 4-chloroflavanone (4Cl-FNN) for 0, 15, 30 and 60 minutes at concentrations of 20, 25 or 30 µg/mL. DMSO was included as a vehicle control.
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pone-0025681-g002: Growth-inhibitory activity of 4-Cl-Flavanone (FNN) against C. neoformans.Agar plate spotting in four 10-fold dilutions after cell exposure to 4-chloroflavanone (4Cl-FNN) for 0, 15, 30 and 60 minutes at concentrations of 20, 25 or 30 µg/mL. DMSO was included as a vehicle control.

Mentions: In contrast, MIC values were found for all of the non-natural flavanones with some having significant antifungal capacity (Table 3). Of the compounds tested, only the 3-hydroxyflavanone failed to provide significant antifungal ability on any of the strains tested. The yeast S. cerevisiae was found to be highly sensitive to 4-chloroflavanone (30 µg/mL) and moderately sensitive to two others (3-fluoro- and 4-fluoro-) with a MIC value of 55 µg/mL. The most resistant of the three fungal species was A. fumigatus and showed only limited growth inhibition with MIC values all greater than 130 µg/mL. One the other hand, three of the four non-natural flavanones tested demonstrated MIC values of approximately 30 µg/mL for the pathogenic C. neoformans. Figure 2 shows serial dilution on agar growth plates of C. neoformans under different exposure times to 4-chloroflavanone and indicates that the effect is not inhibitory but fungacidal.


Development of non-natural flavanones as antimicrobial agents.

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

Growth-inhibitory activity of 4-Cl-Flavanone (FNN) against C. neoformans.Agar plate spotting in four 10-fold dilutions after cell exposure to 4-chloroflavanone (4Cl-FNN) for 0, 15, 30 and 60 minutes at concentrations of 20, 25 or 30 µg/mL. DMSO was included as a vehicle control.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0025681-g002: Growth-inhibitory activity of 4-Cl-Flavanone (FNN) against C. neoformans.Agar plate spotting in four 10-fold dilutions after cell exposure to 4-chloroflavanone (4Cl-FNN) for 0, 15, 30 and 60 minutes at concentrations of 20, 25 or 30 µg/mL. DMSO was included as a vehicle control.
Mentions: In contrast, MIC values were found for all of the non-natural flavanones with some having significant antifungal capacity (Table 3). Of the compounds tested, only the 3-hydroxyflavanone failed to provide significant antifungal ability on any of the strains tested. The yeast S. cerevisiae was found to be highly sensitive to 4-chloroflavanone (30 µg/mL) and moderately sensitive to two others (3-fluoro- and 4-fluoro-) with a MIC value of 55 µg/mL. The most resistant of the three fungal species was A. fumigatus and showed only limited growth inhibition with MIC values all greater than 130 µg/mL. One the other hand, three of the four non-natural flavanones tested demonstrated MIC values of approximately 30 µg/mL for the pathogenic C. neoformans. Figure 2 shows serial dilution on agar growth plates of C. neoformans under different exposure times to 4-chloroflavanone and indicates that the effect is not inhibitory but fungacidal.

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