Antimicrobial and efflux pump inhibitory activity of caffeoylquinic acids from Artemisia absinthium against gram-positive pathogenic bacteria

Traditional antibiotics are increasingly suffering from the emergence of multidrug resistance amongst pathogenic bacteria leading to a range of novel approaches to control microbial infections being investigated as potential alternative treatments. One plausible antimicrobial alternative could be th...

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Published in:	PloS one Vol. 6; no. 4; p. e18127
Main Authors:	Fiamegos, Yiannis C, Kastritis, Panagiotis L, Exarchou, Vassiliki, Han, Haley, Bonvin, Alexandre M J J, Vervoort, Jacques, Lewis, Kim, Hamblin, Michael R, Tegos, George P
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 04-04-2011 Public Library of Science (PLoS)
Subjects:	Acids analogs Analysis Animals Anti-Bacterial Agents - pharmacology Anti-Infective Agents - chemistry Anti-Infective Agents - pharmacology Anti-Infective Agents - toxicity antibiotic-activity Antibiotics Antiinfectives and antibacterials Antimicrobial activity Antimicrobial agents Artemisia absinthium Artemisia absinthium - chemistry ATP-Binding Cassette Transporters - chemistry ATP-Binding Cassette Transporters - metabolism Bacteria Berberine Berberine - metabolism Berberis Bioassays Biofilms Biofilms - drug effects Biological products Biology Caffeoylquinic acid Chemical compounds Chemistry Chlorogenic acid chlorogenic acids Chromatography Clinical isolates Columns (structural) Cytotoxicity derivatives Dermatology Docking Drug Resistance, Multiple - drug effects Drug Synergism Efflux Enterococcus faecalis Glycoproteins Gram-positive bacteria Gram-Positive Bacteria - drug effects Gram-Positive Bacteria - metabolism Gram-Positive Bacteria - physiology Health aspects Health sciences Hemolysis - drug effects Hospitals Humans Infection Infection control Inhibitors Liquid chromatography Magnetic permeability Magnetic resonance Magnetic resonance spectroscopy Mass spectrometry Mass spectroscopy Medicine Microbial drug resistance Microorganisms Models, Molecular Molecular modelling Multidrug resistance N.M.R Natural products NMR nora Nuclear magnetic resonance Nuclear magnetic resonance spectroscopy Pathogens phenolic compounds Phenols Plant extracts Plant Extracts - chemistry Plant Extracts - pharmacology Plant Extracts - toxicity Potentiation protein Protein Conformation Proteins Pseudomonas fluorescens Purification Quinic Acid - analogs & derivatives Quinic Acid - chemistry Quinic Acid - pharmacology Quinic Acid - toxicity Spectroscopy Staphylococcus aureus Substrates transporter United States > US New Mexico Massachusetts
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Summary:	Traditional antibiotics are increasingly suffering from the emergence of multidrug resistance amongst pathogenic bacteria leading to a range of novel approaches to control microbial infections being investigated as potential alternative treatments. One plausible antimicrobial alternative could be the combination of conventional antimicrobial agents/antibiotics with small molecules which block multidrug efflux systems known as efflux pump inhibitors. Bioassay-driven purification and structural determination of compounds from plant sources have yielded a number of pump inhibitors which acted against gram positive bacteria. In this study we report the identification and characterization of 4',5'-O-dicaffeoylquinic acid (4',5'-ODCQA) from Artemisia absinthium as a pump inhibitor with a potential of targeting efflux systems in a wide panel of gram-positive human pathogenic bacteria. Separation and identification of phenolic compounds (chlorogenic acid, 3',5'-ODCQA, 4',5'-ODCQA) was based on hyphenated chromatographic techniques such as liquid chromatography with post column solid-phase extraction coupled with nuclear magnetic resonance spectroscopy and mass spectroscopy. Microbial susceptibility testing and potentiation of well know pump substrates revealed at least two active compounds; chlorogenic acid with weak antimicrobial activity and 4',5'-ODCQA with pump inhibitory activity whereas 3',5'-ODCQA was ineffective. These initial findings were further validated with checkerboard, berberine accumulation efflux assays using efflux-related phenotypes and clinical isolates as well as molecular modeling methodology. These techniques facilitated the direct analysis of the active components from plant extracts, as well as dramatically reduced the time needed to analyze the compounds, without the need for prior isolation. The calculated energetics of the docking poses supported the biological information for the inhibitory capabilities of 4',5'-ODCQA and furthermore contributed evidence that CQAs show a preferential binding to Major Facilitator Super family efflux systems, a key multidrug resistance determinant in gram-positive bacteria.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 Conceived and designed the experiments: YCF KL GPT. Performed the experiments: YCF PLK VE HH. Analyzed the data: YCF PLK AMJJB MRH GPT. Contributed reagents/materials/analysis tools: JV AMJJB KL MRH. Wrote the paper: YCF MRH GPT. Current address: Department of Pathology School of Medicine and Center for Molecular Discovery University of New Mexico, University of New Mexico Health Sciences Center Albuquerque, New Mexico, United States of America
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0018127