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Increasing concerns over the rise in multiply antibiotic resistant bacteria underscore the need for new alternatives to antibiotics. While plants produce an extensive array of active compounds, most show only modest antimicrobial activities.<P> Our goal, therefore, includes testing the ability of extracts of medicinally relevant plants, including Hypericum, Echinacea and Prunella for antimicrobial activity. Bacteria also possess strategies to reduce the effective concentration of antimicrobials, which likely contribute to the weak efficacy of plant-derived compounds. <P>As a consequence we will also test plant extracts in combination with specific inhibitors of multi-drug resistant (MDR) efflux pump proteins as well as agents that increase the membrane permeability of the Gram-negative cell wall, as a means to enhance antimicrobial activity. <P>To be effective in therapeutic treatment of bacterial infection, antimicrobial agents must function in animal tissue and show no toxicity to host tissue. <P>To test the effectiveness of plant compounds, we will use the nematode Caenorhabditis elegans as a model host for bacterial pathogens. Using this system we should be able to detect agents that act by boosting the host innate immunity, which would have been missed by in vitro screening, may be identified.
Non-Technical Summary: Plants have been used medicinally for centuries, although more studies are needed to better assess their efficacy and mechanism of activity. Several published reports indicate a variety of compounds produced by Echinacea and Hypericum exhibit antibiotic-like properties. This is potentially important since antibiotic resistant bacteria are becoming widespread and are having adverse effects on human and animal health. We plan to test the efficacy of plant extracts at killing bacteria both directly and in a simple animal model. The outcome of this study could result in new treatments for prevention and control of pathogenic bacteria in humans and animals. <P> Approach: We will use measurements of minimal inhibitory concentration (MIC) to measure the increase in efficacy of weakly active plant extracts when administered with known MDR pump inhibitors. Tests will be performed on distinct groups of bacterial pathogens, including representative gram-positive bacteria, as well as the common food borne, gram-negative bacteria Salmonella enterica serovar Typhimurium and Escherichia coli. To perform the assays, bacteria will be plated onto nutrient agar plates and small filter discs will be added to the center of each plate. Compounds, including MDR inhibitors, plant extracts and antibiotic controls will be applied to each filter. After incubation the zone of inhibition around each filter disc will be measured. Additional tests will include measuring the concentrations of MDR inhibitors, as well as plant extracts, that show efficacy. A C. elegans screening system will also be used to screen plant-derived compounds. C. elegans will be cultured using the E. coli strain OP50 as a non-pathogenic food source using standard techniques. The system will utilize a strain of C. elegans that is temperature-sensitive (TS) for reproduction so that nematode killing can be directly monitored by counting viable animals without having to account for newly hatched worms.