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.
Highlights
Bacterial pathogens often develop mechanisms of resistance to different chemical compounds over time by adapting their transporter systems to remove toxic compounds, such as drugs and detergents, a mechanism identified over thirty years ago while screening cancer drugs [1,2]
Natural flavanones as bacteriostatic agents To establish a base-line anti-microbial potency of flavanones in general, we first tested the natural flavanones, namely naringenin, pinocembrin and eriodictoyl, for their ability to limit the growth of the gram-negative bacteria E. coli (Table 1)
In the presence of the resistance–nodulation–cell division (RND) efflux pump inhibitors NMP and PABN there was a significant reduction in the growth ability of E. coli
Summary
Bacterial pathogens often develop mechanisms of resistance to different chemical compounds over time by adapting their transporter systems to remove toxic compounds, such as drugs and detergents, a mechanism identified over thirty years ago while screening cancer drugs [1,2]. The latest antibacterial treatments are being developed by screening collections of compounds against a panel of bacterial pathogens in their MDR form and RND mutants to identify improved or novel antibacterial activity [5]. Recent habits in the American diet has shown increased interest in adopting healthy eating behaviors based on Asian and Mediterranean diets in an effort to reduce their risk of heart disease, diabetes, cancer and other lifestyle related disorders [6]. These same diets are often rich in plant polyphenols, such as flavonoids and carotenoids, due to the increased consumption of fruits and vegetables often involved in such diets. Increases to levels of polyphenolic substances have been demonstrated in plants during fungal infection, suggesting that these molecules may be part of the host-defense mechanism [10,11]
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