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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

HeLa cell toxicity to non-natural flavanones.Relative cell viability for HeLa cells after 3 hour and 24 hour incubations in the presence of the natural flavanone naringenin and non-naturals 3-fluoro- (3F-), 4-chloro- (4Cl-), 4-fluoro- (4F-), and 4-fluoro-3-chloro- (4Cl-3Cl-) flavanones (FNN). 5-fluorouracil (5FU) was used as a positive control.
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pone-0025681-g003: HeLa cell toxicity to non-natural flavanones.Relative cell viability for HeLa cells after 3 hour and 24 hour incubations in the presence of the natural flavanone naringenin and non-naturals 3-fluoro- (3F-), 4-chloro- (4Cl-), 4-fluoro- (4F-), and 4-fluoro-3-chloro- (4Cl-3Cl-) flavanones (FNN). 5-fluorouracil (5FU) was used as a positive control.

Mentions: One of the challenges of antifungal therapies is that the close phylogenetic reslationship between fungi and mammals often results in cross-kingdom toxicity. Novel antifungal agents thus must ideally exhibit potent antifungal activity with minimal effect on human cell viability. To address the question of cytotoxicity, cell viability assays of the chemically synthesized drugs were performed with the natural flavanone naringenin used as a benchmark for cell toxicity. As a positive control, 5-fluorouracil (5FU) was used and is widely applied chemotherapeutic agent in gastrointestinal carcinoma [29]. Naringenin deemed to be relatively non-toxic with cell viability at 81.6% after 24 hours (Figure 3) using 150 µg/mL, however the 50% Lethal Dose (LD50) value for 5-FU is 170 µg/mL at 24 hours. Importantly, while the non-natural compounds were shown to be potent anti-microbial agents, the cyotitoxicity was relatively low. The non-natural analogs with fluorine substitutions were less toxic having cell viabilities greater than 70% after 24 hours while those with chlorine substitutions were relatively more cytotoxic.


Development of non-natural flavanones as antimicrobial agents.

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

HeLa cell toxicity to non-natural flavanones.Relative cell viability for HeLa cells after 3 hour and 24 hour incubations in the presence of the natural flavanone naringenin and non-naturals 3-fluoro- (3F-), 4-chloro- (4Cl-), 4-fluoro- (4F-), and 4-fluoro-3-chloro- (4Cl-3Cl-) flavanones (FNN). 5-fluorouracil (5FU) was used as a positive control.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0025681-g003: HeLa cell toxicity to non-natural flavanones.Relative cell viability for HeLa cells after 3 hour and 24 hour incubations in the presence of the natural flavanone naringenin and non-naturals 3-fluoro- (3F-), 4-chloro- (4Cl-), 4-fluoro- (4F-), and 4-fluoro-3-chloro- (4Cl-3Cl-) flavanones (FNN). 5-fluorouracil (5FU) was used as a positive control.
Mentions: One of the challenges of antifungal therapies is that the close phylogenetic reslationship between fungi and mammals often results in cross-kingdom toxicity. Novel antifungal agents thus must ideally exhibit potent antifungal activity with minimal effect on human cell viability. To address the question of cytotoxicity, cell viability assays of the chemically synthesized drugs were performed with the natural flavanone naringenin used as a benchmark for cell toxicity. As a positive control, 5-fluorouracil (5FU) was used and is widely applied chemotherapeutic agent in gastrointestinal carcinoma [29]. Naringenin deemed to be relatively non-toxic with cell viability at 81.6% after 24 hours (Figure 3) using 150 µg/mL, however the 50% Lethal Dose (LD50) value for 5-FU is 170 µg/mL at 24 hours. Importantly, while the non-natural compounds were shown to be potent anti-microbial agents, the cyotitoxicity was relatively low. The non-natural analogs with fluorine substitutions were less toxic having cell viabilities greater than 70% after 24 hours while those with chlorine substitutions were relatively more cytotoxic.

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