Ajoene, a sulfur-rich molecule from garlic, inhibits genes controlled by quorum sensing

Tim Holm Jakobsen; Maria van Gennip; Richard Kerry Phipps; Meenakshi Sundaram Shanmugham; Louise Dahl Hultqvist; Morten Alhede; Mette Eline Skindersoe; Thomas Bovbjerg Rasmussen; Karlheinz Friedrich; Friedrich Uthe; Peter Østrup Jensen; Claus Moser; Kristian Fog Nielsen; Leo Eberl; Thomas Ostenfeld Larsen; David Ackland Tanner; Niels Høiby; Thomas Bjarnsholt; Michael Givskov; Maria Alhede

doi:10.1128/AAC.05919-11

Ajoene, a sulfur-rich molecule from garlic, inhibits genes controlled by quorum sensing

Tim Holm Jakobsen, Maria van Gennip, Richard Kerry Phipps, Meenakshi Sundaram Shanmugham, Louise Dahl Hultqvist, Morten Alhede, Mette Eline Skindersoe, Thomas Bovbjerg Rasmussen, Karlheinz Friedrich, Friedrich Uthe, Peter Østrup Jensen, Claus Moser, Kristian Fog Nielsen, Leo Eberl, Thomas Ostenfeld Larsen, David Ackland Tanner, Niels Høiby, Thomas Bjarnsholt, Michael Givskov, Maria Alhede

269 Citationer (Scopus)

Abstract

In relation to emerging multiresistant bacteria, development of antimicrobials and new treatment strategies of infections should be expected to become a high-priority research area. Quorum sensing (QS), a communication system used by pathogenic bacteria like Pseudomonas aeruginosa to synchronize the expression of specific genes involved in pathogenicity, is a possible drug target. Previous in vitro and in vivo studies revealed a significant inhibition of P. aeruginosa QS by crude garlic extract. By bioassay-guided fractionation of garlic extracts, we determined the primary QS inhibitor present in garlic to be ajoene, a sulfur-containing compound with potential as an antipathogenic drug. By comprehensive in vitro and in vivo studies, the effect of synthetic ajoene toward P. aeruginosa was elucidated. DNA microarray studies of ajoene-treated P. aeruginosa cultures revealed a concentration-dependent attenuation of a few but central QS-controlled virulence factors, including rhamnolipid. Furthermore, ajoene treatment of in vitro biofilms demonstrated a clear synergistic, antimicrobial effect with tobramycin on biofilm killing and a cease in lytic necrosis of polymorphonuclear leukocytes. Furthermore, in a mouse model of pulmonary infection, a significant clearing of infecting P. aeruginosa was detected in ajoene-treated mice compared to a nontreated control group. This study adds to the list of examples demonstrating the potential of QS-interfering compounds in the treatment of bacterial infections.

Originalsprog	Engelsk
Tidsskrift	Antimicrobial Agents and Chemotherapy
Vol/bind	56
Udgave nummer	5
Sider (fra-til)	2314-25
Antal sider	12
ISSN	1098-6596
DOI	https://doi.org/10.1128/AAC.05919-11
Status	Udgivet - maj 2012

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10.1128/AAC.05919-11

Citationsformater

Jakobsen, T. H., van Gennip, M., Phipps, R. K., Shanmugham, M. S., Hultqvist, L. D., Alhede, M., Skindersoe, M. E., Rasmussen, T. B., Friedrich, K., Uthe, F., Jensen, P. Ø., Moser, C., Nielsen, K. F., Eberl, L., Larsen, T. O., Tanner, D. A., Høiby, N., Bjarnsholt, T., Givskov, M., & Alhede, M. (2012). Ajoene, a sulfur-rich molecule from garlic, inhibits genes controlled by quorum sensing. Antimicrobial Agents and Chemotherapy, 56(5), 2314-25. https://doi.org/10.1128/AAC.05919-11

Jakobsen, TH, van Gennip, M, Phipps, RK, Shanmugham, MS, Hultqvist, LD, Alhede, M, Skindersoe, ME, Rasmussen, TB, Friedrich, K, Uthe, F, Jensen, PØ , Moser, C , Nielsen, KF, Eberl, L, Larsen, TO, Tanner, DA, Høiby, N , Bjarnsholt, T , Givskov, M & Alhede, M 2012, 'Ajoene, a sulfur-rich molecule from garlic, inhibits genes controlled by quorum sensing', Antimicrobial Agents and Chemotherapy, bind 56, nr. 5, s. 2314-25. https://doi.org/10.1128/AAC.05919-11

@article{941bce28926f4c5b8a3f2638ed4f02ae,

title = "Ajoene, a sulfur-rich molecule from garlic, inhibits genes controlled by quorum sensing",

abstract = "In relation to emerging multiresistant bacteria, development of antimicrobials and new treatment strategies of infections should be expected to become a high-priority research area. Quorum sensing (QS), a communication system used by pathogenic bacteria like Pseudomonas aeruginosa to synchronize the expression of specific genes involved in pathogenicity, is a possible drug target. Previous in vitro and in vivo studies revealed a significant inhibition of P. aeruginosa QS by crude garlic extract. By bioassay-guided fractionation of garlic extracts, we determined the primary QS inhibitor present in garlic to be ajoene, a sulfur-containing compound with potential as an antipathogenic drug. By comprehensive in vitro and in vivo studies, the effect of synthetic ajoene toward P. aeruginosa was elucidated. DNA microarray studies of ajoene-treated P. aeruginosa cultures revealed a concentration-dependent attenuation of a few but central QS-controlled virulence factors, including rhamnolipid. Furthermore, ajoene treatment of in vitro biofilms demonstrated a clear synergistic, antimicrobial effect with tobramycin on biofilm killing and a cease in lytic necrosis of polymorphonuclear leukocytes. Furthermore, in a mouse model of pulmonary infection, a significant clearing of infecting P. aeruginosa was detected in ajoene-treated mice compared to a nontreated control group. This study adds to the list of examples demonstrating the potential of QS-interfering compounds in the treatment of bacterial infections.",

keywords = "Animals, Anti-Bacterial Agents, Biofilms, Chemical Fractionation, Disulfides, Drug Synergism, Garlic, Gene Expression Regulation, Bacterial, Genes, Reporter, Glycolipids, Mice, Neutrophils, Plant Extracts, Pseudomonas Infections, Pseudomonas aeruginosa, Quorum Sensing, Respiratory Tract Infections, Tobramycin, Virulence Factors",

author = "Jakobsen, {Tim Holm} and {van Gennip}, Maria and Phipps, {Richard Kerry} and Shanmugham, {Meenakshi Sundaram} and Hultqvist, {Louise Dahl} and Morten Alhede and Skindersoe, {Mette Eline} and Rasmussen, {Thomas Bovbjerg} and Karlheinz Friedrich and Friedrich Uthe and Jensen, {Peter {\O}strup} and Claus Moser and Nielsen, {Kristian Fog} and Leo Eberl and Larsen, {Thomas Ostenfeld} and Tanner, {David Ackland} and Niels H{\o}iby and Thomas Bjarnsholt and Michael Givskov and Maria Alhede",

year = "2012",

month = may,

doi = "10.1128/AAC.05919-11",

language = "English",

volume = "56",

pages = "2314--25",

journal = "Antimicrobial Agents and Chemotherapy",

issn = "1098-6596",

publisher = "American Society for Microbiology",

number = "5",

}

TY - JOUR

T1 - Ajoene, a sulfur-rich molecule from garlic, inhibits genes controlled by quorum sensing

AU - Jakobsen, Tim Holm

AU - van Gennip, Maria

AU - Phipps, Richard Kerry

AU - Shanmugham, Meenakshi Sundaram

AU - Hultqvist, Louise Dahl

AU - Alhede, Morten

AU - Skindersoe, Mette Eline

AU - Rasmussen, Thomas Bovbjerg

AU - Friedrich, Karlheinz

AU - Uthe, Friedrich

AU - Jensen, Peter Østrup

AU - Moser, Claus

AU - Nielsen, Kristian Fog

AU - Eberl, Leo

AU - Larsen, Thomas Ostenfeld

AU - Tanner, David Ackland

AU - Høiby, Niels

AU - Bjarnsholt, Thomas

AU - Givskov, Michael

AU - Alhede, Maria

PY - 2012/5

Y1 - 2012/5

N2 - In relation to emerging multiresistant bacteria, development of antimicrobials and new treatment strategies of infections should be expected to become a high-priority research area. Quorum sensing (QS), a communication system used by pathogenic bacteria like Pseudomonas aeruginosa to synchronize the expression of specific genes involved in pathogenicity, is a possible drug target. Previous in vitro and in vivo studies revealed a significant inhibition of P. aeruginosa QS by crude garlic extract. By bioassay-guided fractionation of garlic extracts, we determined the primary QS inhibitor present in garlic to be ajoene, a sulfur-containing compound with potential as an antipathogenic drug. By comprehensive in vitro and in vivo studies, the effect of synthetic ajoene toward P. aeruginosa was elucidated. DNA microarray studies of ajoene-treated P. aeruginosa cultures revealed a concentration-dependent attenuation of a few but central QS-controlled virulence factors, including rhamnolipid. Furthermore, ajoene treatment of in vitro biofilms demonstrated a clear synergistic, antimicrobial effect with tobramycin on biofilm killing and a cease in lytic necrosis of polymorphonuclear leukocytes. Furthermore, in a mouse model of pulmonary infection, a significant clearing of infecting P. aeruginosa was detected in ajoene-treated mice compared to a nontreated control group. This study adds to the list of examples demonstrating the potential of QS-interfering compounds in the treatment of bacterial infections.

AB - In relation to emerging multiresistant bacteria, development of antimicrobials and new treatment strategies of infections should be expected to become a high-priority research area. Quorum sensing (QS), a communication system used by pathogenic bacteria like Pseudomonas aeruginosa to synchronize the expression of specific genes involved in pathogenicity, is a possible drug target. Previous in vitro and in vivo studies revealed a significant inhibition of P. aeruginosa QS by crude garlic extract. By bioassay-guided fractionation of garlic extracts, we determined the primary QS inhibitor present in garlic to be ajoene, a sulfur-containing compound with potential as an antipathogenic drug. By comprehensive in vitro and in vivo studies, the effect of synthetic ajoene toward P. aeruginosa was elucidated. DNA microarray studies of ajoene-treated P. aeruginosa cultures revealed a concentration-dependent attenuation of a few but central QS-controlled virulence factors, including rhamnolipid. Furthermore, ajoene treatment of in vitro biofilms demonstrated a clear synergistic, antimicrobial effect with tobramycin on biofilm killing and a cease in lytic necrosis of polymorphonuclear leukocytes. Furthermore, in a mouse model of pulmonary infection, a significant clearing of infecting P. aeruginosa was detected in ajoene-treated mice compared to a nontreated control group. This study adds to the list of examples demonstrating the potential of QS-interfering compounds in the treatment of bacterial infections.

KW - Animals

KW - Anti-Bacterial Agents

KW - Biofilms

KW - Chemical Fractionation

KW - Disulfides

KW - Drug Synergism

KW - Garlic

KW - Gene Expression Regulation, Bacterial

KW - Genes, Reporter

KW - Glycolipids

KW - Mice

KW - Neutrophils

KW - Plant Extracts

KW - Pseudomonas Infections

KW - Pseudomonas aeruginosa

KW - Quorum Sensing

KW - Respiratory Tract Infections

KW - Tobramycin

KW - Virulence Factors

U2 - 10.1128/AAC.05919-11

DO - 10.1128/AAC.05919-11

M3 - Journal article

C2 - 22314537

SN - 1098-6596

VL - 56

SP - 2314

EP - 2325

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 5

ER -

Ajoene, a sulfur-rich molecule from garlic, inhibits genes controlled by quorum sensing

Abstract

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