Antimicrobial and Efflux Pump Inhibitory Activity of Caffeoylquinic Acids from Artemisia absinthium against Gram-Positive Pathogenic Bacteria
Background: 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 alternat...
| Main Authors: | , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Public Library of Science
2011
|
| Online Access: | http://hdl.handle.net/1721.1/65871 |
| _version_ | 1811069647548579840 |
|---|---|
| author | 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. |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology 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. |
| author_sort | Fiamegos, Yiannis C. |
| collection | MIT |
| description | Background:
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.
Methodology/Principal Findings:
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 intitial findings were further validated with checkerboard, berberine accumulation efflux assays using efflux-related phenotypes and clinical isolates as well as molecular modeling methodology.
Conclusions/Significance:
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. |
| first_indexed | 2024-09-23T08:13:42Z |
| format | Article |
| id | mit-1721.1/65871 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:13:42Z |
| publishDate | 2011 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/658712022-09-30T08:26:44Z Antimicrobial and Efflux Pump Inhibitory Activity of Caffeoylquinic Acids from Artemisia absinthium against Gram-Positive Pathogenic Bacteria 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. Harvard University--MIT Division of Health Sciences and Technology Hamblin, Michael R. Hamblin, Michael R. Background: 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. Methodology/Principal Findings: 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 intitial findings were further validated with checkerboard, berberine accumulation efflux assays using efflux-related phenotypes and clinical isolates as well as molecular modeling methodology. Conclusions/Significance: 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. National Institutes of Health (U.S.) (grant R01GM59903) National Institutes of Health (U.S.) (grant R01AI050875) Netherlands Organization for Scientific Research (VICI grant 700.56.442) Massachusetts Technology Transfer Center (MTTC) National Institutes of Health (U.S.) (grant 5U54MH084690-02) 2011-09-16T17:53:10Z 2011-09-16T17:53:10Z 2011-04 2010-10 Article http://purl.org/eprint/type/JournalArticle 1932-6203 http://hdl.handle.net/1721.1/65871 Fiamegos YC, Kastritis PL, Exarchou V, Han H, Bonvin AMJJ, et al. (2011) Antimicrobial and Efflux Pump Inhibitory Activity of Caffeoylquinic Acids from Artemisia absinthium against Gram-Positive Pathogenic Bacteria. PLoS ONE 6(4): e18127. doi:10.1371/journal.pone.0018127 en_US http://dx.doi.org/10.1371/journal.pone.0018127 PLoS ONE Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | 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. Antimicrobial and Efflux Pump Inhibitory Activity of Caffeoylquinic Acids from Artemisia absinthium against Gram-Positive Pathogenic Bacteria |
| title | Antimicrobial and Efflux Pump Inhibitory Activity of Caffeoylquinic Acids from Artemisia absinthium against Gram-Positive Pathogenic Bacteria |
| title_full | Antimicrobial and Efflux Pump Inhibitory Activity of Caffeoylquinic Acids from Artemisia absinthium against Gram-Positive Pathogenic Bacteria |
| title_fullStr | Antimicrobial and Efflux Pump Inhibitory Activity of Caffeoylquinic Acids from Artemisia absinthium against Gram-Positive Pathogenic Bacteria |
| title_full_unstemmed | Antimicrobial and Efflux Pump Inhibitory Activity of Caffeoylquinic Acids from Artemisia absinthium against Gram-Positive Pathogenic Bacteria |
| title_short | Antimicrobial and Efflux Pump Inhibitory Activity of Caffeoylquinic Acids from Artemisia absinthium against Gram-Positive Pathogenic Bacteria |
| title_sort | antimicrobial and efflux pump inhibitory activity of caffeoylquinic acids from artemisia absinthium against gram positive pathogenic bacteria |
| url | http://hdl.handle.net/1721.1/65871 |
| work_keys_str_mv | AT fiamegosyiannisc antimicrobialandeffluxpumpinhibitoryactivityofcaffeoylquinicacidsfromartemisiaabsinthiumagainstgrampositivepathogenicbacteria AT kastritispanagiotisl antimicrobialandeffluxpumpinhibitoryactivityofcaffeoylquinicacidsfromartemisiaabsinthiumagainstgrampositivepathogenicbacteria AT exarchouvassiliki antimicrobialandeffluxpumpinhibitoryactivityofcaffeoylquinicacidsfromartemisiaabsinthiumagainstgrampositivepathogenicbacteria AT hanhaley antimicrobialandeffluxpumpinhibitoryactivityofcaffeoylquinicacidsfromartemisiaabsinthiumagainstgrampositivepathogenicbacteria AT bonvinalexandremjj antimicrobialandeffluxpumpinhibitoryactivityofcaffeoylquinicacidsfromartemisiaabsinthiumagainstgrampositivepathogenicbacteria AT vervoortjacques antimicrobialandeffluxpumpinhibitoryactivityofcaffeoylquinicacidsfromartemisiaabsinthiumagainstgrampositivepathogenicbacteria AT lewiskim antimicrobialandeffluxpumpinhibitoryactivityofcaffeoylquinicacidsfromartemisiaabsinthiumagainstgrampositivepathogenicbacteria AT hamblinmichaelr antimicrobialandeffluxpumpinhibitoryactivityofcaffeoylquinicacidsfromartemisiaabsinthiumagainstgrampositivepathogenicbacteria AT tegosgeorgep antimicrobialandeffluxpumpinhibitoryactivityofcaffeoylquinicacidsfromartemisiaabsinthiumagainstgrampositivepathogenicbacteria |