Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 5 February 1999:
Vol. 283. no. 5403, pp. 854 - 857
DOI: 10.1126/science.283.5403.854
Prev | Table of Contents | Next

Reports

Mycolactone: A Polyketide Toxin from Mycobacterium ulcerans Required for Virulence

Kathleen M. George, 1 Delphi Chatterjee, 2 Geewananda Gunawardana, 3 Diane Welty, 1 John Hayman, 4 Richard Lee, 5 P. L. C. Small 1

Mycobacterium ulcerans is the causative agent of Buruli ulcer, a severe human skin disease that occurs primarily in Africa and Australia. Infection with M. ulcerans results in persistent severe necrosis without an acute inflammatory response. The presence of histopathological changes distant from the site of infection suggested that pathogenesis might be toxin mediated. A polyketide-derived macrolide designated mycolactone was isolated that causes cytopathicity and cell cycle arrest in cultured L929 murine fibroblasts. Intradermal inoculation of purified toxin into guinea pigs produced a lesion similar to that of Buruli ulcer in humans. This toxin may represent one of a family of virulence factors associated with pathology in mycobacterial diseases such as leprosy and tuberculosis.

1 Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
2 Department of Microbiology, Colorado State University, Fort Collins, CO 80523-1677, USA.
3 Abbott Laboratories, Abbott Park, IL 60064, USA.
4 Box Hill Hospital, Box Hill, Victoria 3128 Australia.
5 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
*To whom correspondence should be addressed. E-mail: psmall{at}nih.gov

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Functional Limitations after Surgical or Antibiotic Treatment for Buruli Ulcer in Benin.
Y. Barogui, R. C. Johnson, T. S. van der Werf, G. Sopoh, A. Dossou, P. U. Dijkstra, and Y. Stienstra (2009)
Am J Trop Med Hyg 81, 82-87
   Abstract »    Full Text »    PDF »
Mycolactone Inhibits Monocyte Cytokine Production by a Posttranscriptional Mechanism.
R. E. Simmonds, F. V. Lali, T. Smallie, P. L. C. Small, and B. M. Foxwell (2009)
J. Immunol. 182, 2194-2202
   Abstract »    Full Text »    PDF »
Dynamics of the Cytokine Response to Mycobacterium ulcerans during Antibiotic Treatment for M. ulcerans Disease (Buruli Ulcer) in Humans.
F. S. Sarfo, R. O. Phillips, E. Ampadu, F. Sarpong, E. Adentwe, and M. Wansbrough-Jones (2009)
Clin. Vaccine Immunol. 16, 61-65
   Abstract »    Full Text »    PDF »
Persistent Association of Mycobacterium ulcerans with West African Predaceous Insects of the Family Belostomatidae.
L. Mosi, H. Williamson, J. R. Wallace, R. W. Merritt, and P. L. C. Small (2008)
Appl. Envir. Microbiol. 74, 7036-7042
   Abstract »    Full Text »    PDF »
Mycolactone Is Responsible for the Painlessness of Mycobacterium ulcerans Infection (Buruli Ulcer) in a Murine Study.
J. En, M. Goto, K. Nakanaga, M. Higashi, N. Ishii, H. Saito, S. Yonezawa, H. Hamada, and P. L. C. Small (2008)
Infect. Immun. 76, 2002-2007
   Abstract »    Full Text »    PDF »
Insights from the complete genome sequence of Mycobacterium marinum on the evolution of Mycobacterium tuberculosis.
T. P. Stinear, T. Seemann, P. F. Harrison, G. A. Jenkin, J. K. Davies, P. D.R. Johnson, Z. Abdellah, C. Arrowsmith, T. Chillingworth, C. Churcher, et al. (2008)
Genome Res. 18, 729-741
   Abstract »    Full Text »    PDF »
A rapid approach to lipid profiling of mycobacteria using 2D HSQC NMR maps.
E. A. Mahrous, R. B. Lee, and R. E. Lee (2008)
J. Lipid Res. 49, 455-463
   Abstract »    Full Text »    PDF »
Promising Clinical Efficacy of Streptomycin-Rifampin Combination for Treatment of Buruli Ulcer (Mycobacterium ulcerans Disease).
A. Chauty, M.-F. Ardant, A. Adeye, H. Euverte, A. Guedenon, C. Johnson, J. Aubry, E. Nuermberger, and J. Grosset (2007)
Antimicrob. Agents Chemother. 51, 4029-4035
   Abstract »    Full Text »    PDF »
"Mycobacterium ulcerans subsp. shinshuense" Isolated from a Skin Ulcer Lesion: Identification Based on 16S rRNA Gene Sequencing.
K. Nakanaga, N. Ishii, K. Suzuki, K. Tanigawa, M. Goto, T. Okabe, H. Imada, A. Kodama, T. Iwamoto, H. Takahashi, et al. (2007)
J. Clin. Microbiol. 45, 3840-3843
   Abstract »    Full Text »    PDF »
Genomics of Actinobacteria: Tracing the Evolutionary History of an Ancient Phylum.
M. Ventura, C. Canchaya, A. Tauch, G. Chandra, G. F. Fitzgerald, K. F. Chater, and D. van Sinderen (2007)
Microbiol. Mol. Biol. Rev. 71, 495-548
   Abstract »    Full Text »    PDF »
Mycolactone-Mediated Inhibition of Tumor Necrosis Factor Production by Macrophages Infected with Mycobacterium ulcerans Has Implications for the Control of Infection.
E. Torrado, S. Adusumilli, A. G. Fraga, P. L. C. Small, A. G. Castro, and J. Pedrosa (2007)
Infect. Immun. 75, 3979-3988
   Abstract »    Full Text »    PDF »
Selective suppression of dendritic cell functions by Mycobacterium ulcerans toxin mycolactone.
E. Coutanceau, J. Decalf, A. Martino, A. Babon, N. Winter, S. T. Cole, M. L. Albert, and C. Demangel (2007)
J. Exp. Med. 204, 1395-1403
   Abstract »    Full Text »    PDF »
A Booster Vaccination with Mycobacterium bovis BCG Does Not Increase the Protective Effect of the Vaccine against Experimental Mycobacterium ulcerans Infection in Mice.
A. Tanghe, P.-Y. Adnet, T. Gartner, and K. Huygen (2007)
Infect. Immun. 75, 2642-2644
   Abstract »    Full Text »    PDF »
Evidence for an Intramacrophage Growth Phase of Mycobacterium ulcerans.
E. Torrado, A. G. Fraga, A. G. Castro, P. Stragier, W. M. Meyers, F. Portaels, M. T. Silva, and J. Pedrosa (2007)
Infect. Immun. 75, 977-987
   Abstract »    Full Text »    PDF »
Use of the Immunodominant 18-Kilodalton Small Heat Shock Protein as a Serological Marker for Exposure to Mycobacterium ulcerans.
D. Diaz, H. Dobeli, D. Yeboah-Manu, E. Mensah-Quainoo, A. Friedlein, N. Soder, S. Rondini, T. Bodmer, and G. Pluschke (2006)
Clin. Vaccine Immunol. 13, 1314-1321
   Abstract »    Full Text »    PDF »
Globally Distributed Mycobacterial Fish Pathogens Produce a Novel Plasmid-Encoded Toxic Macrolide, Mycolactone F.
B. S. Ranger, E. A. Mahrous, L. Mosi, S. Adusumilli, R. E. Lee, A. Colorni, M. Rhodes, and P. L. C. Small (2006)
Infect. Immun. 74, 6037-6045
   Abstract »    Full Text »    PDF »
What Does Detection of Mycobacterium ulcerans DNA in the Margin of an Excised Buruli Ulcer Lesion Tell Us?.
S. Rondini, E. Mensah-Quainoo, T. Junghanss, and G. Pluschke (2006)
J. Clin. Microbiol. 44, 4273-4275
   Abstract »    Full Text »    PDF »
How to become a uropathogen: Comparative genomic analysis of extraintestinal pathogenic Escherichia coli strains.
E. Brzuszkiewicz, H. Bruggemann, H. Liesegang, M. Emmerth, T. Olschlager, G. Nagy, K. Albermann, C. Wagner, C. Buchrieser, L. Emody, et al. (2006)
PNAS 103, 12879-12884
   Abstract »    Full Text »    PDF »
Systemic suppression of interferon-{gamma} responses in Buruli ulcer patients resolves after surgical excision of the lesions caused by the extracellular pathogen Mycobacterium ulcerans.
D. Yeboah-Manu, E. Peduzzi, E. Mensah-Quainoo, A. Asante-Poku, D. Ofori-Adjei, G. Pluschke, and C. A. Daubenberger (2006)
J. Leukoc. Biol. 79, 1150-1156
   Abstract »    Full Text »    PDF »
Cytokine mRNA Expression in Mycobacteriam ulcerans-Infected Human Skin and Correlation with Local Inflammatory Response..
R. Phillips, C. Horsfield, J. Mangan, K. Laing, S. Etuaful, P. Awuah, K. Nyarko, F. Osei-Sarpong, P. Butcher, S. Lucas, et al. (2006)
Infect. Immun. 74, 2917-2924
   Abstract »    Full Text »    PDF »
Nerve Damage in Mycobacterium ulcerans-Infected Mice: Probable Cause of Painlessness in Buruli Ulcer.
M. Goto, K. Nakanaga, T. Aung, T. Hamada, N. Yamada, M. Nomoto, S. Kitajima, N. Ishii, S. Yonezawa, and H. Saito (2006)
Am. J. Pathol. 168, 805-811
   Abstract »    Full Text »    PDF »
Host range of 14 mycobacteriophages in Mycobacterium ulcerans and seven other mycobacteria including Mycobacterium tuberculosis - application for identification and susceptibility testing.
J. Rybniker, S. Kramme, and P. L. Small (2006)
J. Med. Microbiol. 55, 37-42
   Abstract »    Full Text »    PDF »
Infection with Mycobacterium ulcerans Induces Persistent Inflammatory Responses in Mice.
M. S. Oliveira, A. G. Fraga, E. Torrado, A. G. Castro, J. P. Pereira, A. L. Filho, F. Milanezi, F. C. Schmitt, W. M. Meyers, F. Portaels, et al. (2005)
Infect. Immun. 73, 6299-6310
   Abstract »    Full Text »    PDF »
HIGH RATES OF APOPTOSIS IN HUMAN MYCOBACTERIUM ULCERANS CULTURE-POSITIVE BURULI ULCER SKIN LESIONS.
D. S. WALSH, W. M. MEYERS, F. PORTAELS, J. E. LANE, D. MONGKOLSIRICHAIKUL, K. HUSSEM, P. GOSI, and K. S. A. MYINT (2005)
Am J Trop Med Hyg 73, 410-415
   Abstract »    Full Text »    PDF »
Buruli ulcer.
M. Wansbrough-Jones and R. Phillips (2005)
BMJ 330, 1402-1403
   Full Text »    PDF »
A Newly Discovered Mycobacterial Pathogen Isolated from Laboratory Colonies of Xenopus Species with Lethal Infections Produces a Novel Form of Mycolactone, the Mycobacterium ulcerans Macrolide Toxin.
A. Mve-Obiang, R. E. Lee, E. S. Umstot, K. A. Trott, T. C. Grammer, J. M. Parker, B. S. Ranger, R. Grainger, E. A. Mahrous, and P. L. C. Small (2005)
Infect. Immun. 73, 3307-3312
   Abstract »    Full Text »    PDF »
Genotyping Mycobacterium ulcerans and Mycobacterium marinum by Using Mycobacterial Interspersed Repetitive Units.
P. Stragier, A. Ablordey, W. M. Meyers, and F. Portaels (2005)
J. Bacteriol. 187, 1639-1647
   Abstract »    Full Text »    PDF »
Common Evolutionary Origin for the Unstable Virulence Plasmid pMUM Found in Geographically Diverse Strains of Mycobacterium ulcerans.
T. P. Stinear, H. Hong, W. Frigui, M. J. Pryor, R. Brosch, T. Garnier, P. F. Leadlay, and S. T. Cole (2005)
J. Bacteriol. 187, 1668-1676
   Abstract »    Full Text »    PDF »
From the Cover: Giant plasmid-encoded polyketide synthases produce the macrolide toxin of Mycobacterium ulcerans.
T. P. Stinear, A. Mve-Obiang, P. L. C. Small, W. Frigui, M. J. Pryor, R. Brosch, G. A. Jenkin, P. D. R. Johnson, J. K. Davies, R. E. Lee, et al. (2004)
PNAS 101, 1345-1349
   Abstract »    Full Text »    PDF »
Necrotic Death of Rhodococcus equi-Infected Macrophages Is Regulated by Virulence-Associated Plasmids.
A. Luhrmann, N. Mauder, T. Sydor, E. Fernandez-Mora, J. Schulze-Luehrmann, S. Takai, and A. Haas (2004)
Infect. Immun. 72, 853-862
   Abstract »    Full Text »    PDF »
Differential Production of Systemic and Intralesional Gamma Interferon and Interleukin-10 in Nodular and Ulcerative Forms of Buruli Disease.
G. Prevot, E. Bourreau, H. Pascalis, R. Pradinaud, A. Tanghe, K. Huygen, and P. Launois (2004)
Infect. Immun. 72, 958-965
   Abstract »    Full Text »    PDF »
Aquatic Plants Stimulate the Growth of and Biofilm Formation by Mycobacterium ulcerans in Axenic Culture and Harbor These Bacteria in the Environment.
L. Marsollier, T. Stinear, J. Aubry, J. P. Saint Andre, R. Robert, P. Legras, A.-L. Manceau, C. Audrain, S. Bourdon, H. Kouakou, et al. (2004)
Appl. Envir. Microbiol. 70, 1097-1103
   Abstract »    Full Text »    PDF »
Mycobacterium bovis BCG Vaccination as Prophylaxis against Mycobacterium ulcerans Osteomyelitis in Buruli Ulcer Disease.
F. Portaels, J. Aguiar, M. Debacker, A. Guedenon, C. Steunou, C. Zinsou, and W. M. Meyers (2004)
Infect. Immun. 72, 62-65
   Abstract »    Full Text »    PDF »
Analysis of Mycobacterium Species for the Presence of a Macrolide Toxin, Mycolactone.
A. K. Daniel, R. E. Lee, F. Portaels, and P. L. C. Small (2004)
Infect. Immun. 72, 123-132
   Abstract »    Full Text »    PDF »
Subtractive Hybridization Reveals a Type I Polyketide Synthase Locus Specific to Mycobacterium ulcerans.
G. A. Jenkin, T. P. Stinear, P. D. R. Johnson, and J. K. Davies (2003)
J. Bacteriol. 185, 6870-6882
   Abstract »    Full Text »    PDF »
Development and Application of Real-Time PCR Assay for Quantification of Mycobacterium ulcerans DNA.
S. Rondini, E. Mensah-Quainoo, H. Troll, T. Bodmer, and G. Pluschke (2003)
J. Clin. Microbiol. 41, 4231-4237
   Abstract »    Full Text »    PDF »
A postgenomic method for predicting essential genes at subsaturation levels of mutagenesis: Application to Mycobacterium tuberculosis.
G. Lamichhane, M. Zignol, N. J. Blades, D. E. Geiman, A. Dougherty, J. Grosset, K. W. Broman, and W. R. Bishai (2003)
PNAS 100, 7213-7218
   Abstract »    Full Text »    PDF »
Structural and Functional Cellular Changes Induced by Burkholderia pseudomallei Rhamnolipid.
S. Haussler, M. Rohde, N. von Neuhoff, M. Nimtz, and I. Steinmetz (2003)
Infect. Immun. 71, 2970-2975
   Abstract »    Full Text »    PDF »
Isolation of Three Mycobacterium ulcerans Strains Resistant to Rifampin after Experimental Chemotherapy of Mice.
L. Marsollier, N. Honore, P. Legras, A. L. Manceau, H. Kouakou, B. Carbonnelle, and S. T. Cole (2003)
Antimicrob. Agents Chemother. 47, 1228-1232
   Abstract »    Full Text »    PDF »
Heterogeneity of Mycolactones Produced by Clinical Isolates of Mycobacterium ulcerans: Implications for Virulence.
A. Mve-Obiang, R. E. Lee, F. Portaels, and P. L. C. Small (2003)
Infect. Immun. 71, 774-783
   Abstract »    Full Text »    PDF »
Involvement of the fadD33 gene in the growth of Mycobacterium tuberculosis in the liver of BALB/c mice.
L. Rindi, L. Fattorini, D. Bonanni, E. Iona, G. Freer, D. Tan, G. Deho, G. Orefici, and C. Garzelli (2002)
Microbiology 148, 3873-3880
   Abstract »    Full Text »    PDF »
Prophylactic Effect of Mycobacterium bovis BCG Vaccination against Osteomyelitis in Children with Mycobacterium ulcerans Disease (Buruli Ulcer).
F. Portaels, J. Aguiar, M. Debacker, C. Steunou, C. Zinsou, A. Guedenon, and W. M. Meyers (2002)
Clin. Vaccine Immunol. 9, 1389-1391
   Abstract »    Full Text »    PDF »
Cytokine Profiles of Patients Infected with Mycobacterium ulcerans and Unaffected Household Contacts.
T. M. Gooding, P. D. R. Johnson, M. Smith, A. S. Kemp, and R. M. Robins-Browne (2002)
Infect. Immun. 70, 5562-5567
   Abstract »    Full Text »    PDF »
Buruli ulcer: the third most common mycobacterial infection.
E. Weir (2002)
Can. Med. Assoc. J. 166, 1691
   Full Text »    PDF »
Mycobacterium tuberculosis WhiB3 interacts with RpoV to affect host survival but is dispensable for in vivo growth.
A. J. C. Steyn, D. M. Collins, M. K. Hondalus, W. R. Jacobs Jr., R. P. Kawakami, and B. R. Bloom (2002)
PNAS 99, 3147-3152
   Abstract »    Full Text »    PDF »
Potential of rifamides to inhibit TNF-induced NF-{kappa}B activation.
A. A. Pahlevan, D. J. M. Wright, L. Bradley, C. Smith, and B. M. J. Foxwell (2002)
J. Antimicrob. Chemother. 49, 531-534
   Abstract »    Full Text »    PDF »
Activities of New Macrolides and Fluoroquinolones against Mycobacterium ulcerans Infection in Mice.
A. Bentoucha, J. Robert, H. Dega, N. Lounis, V. Jarlier, and J. Grosset (2001)
Antimicrob. Agents Chemother. 45, 3109-3112
   Abstract »    Full Text »    PDF »
Mycobacterium ulcerans Cytotoxicity in an Adipose Cell Model.
K. M. Dobos, P. L. Small, M. Deslauriers, F. D. Quinn, and C. H. King (2001)
Infect. Immun. 69, 7182-7186
   Abstract »    Full Text »    PDF »
Protective Efficacy of a DNA Vaccine Encoding Antigen 85A from Mycobacterium bovis BCG against Buruli Ulcer.
A. Tanghe, J. Content, J.-P. Van Vooren, F. Portaels, and K. Huygen (2001)
Infect. Immun. 69, 5403-5411
   Abstract »    Full Text »    PDF »
Identification of two Mycobacterium avium subspecies paratuberculosis gene products differentially recognised by sera from rabbits immunised with live mycobacteria but not heat-killed mycobacteria.
J. P. BANNANTINE and J. R. STABEL (2001)
J. Med. Microbiol. 50, 795-804
   Abstract »    Full Text »    PDF »
Comparing Genomes within the Species Mycobacterium tuberculosis.
M. Kato-Maeda, J. T. Rhee, T. R. Gingeras, H. Salamon, J. Drenkow, N. Smittipat, and P. M. Small (2001)
Genome Res. 11, 547-554
   Abstract »    Full Text »
M. tuberculosis: immunology and vaccination.
G.A.W. Rook, G. Seah, and A. Ustianowski (2001)
Eur. Respir. J. 17, 537-557
   Abstract »    Full Text »    PDF »
Immune Response to Infection with Mycobacterium ulcerans.
T. M. Gooding, P. D. R. Johnson, D. E. Campbell, J. A. Hayman, E. L. Hartland, A. S. Kemp, and R. M. Robins-Browne (2001)
Infect. Immun. 69, 1704-1707
   Abstract »    Full Text »    PDF »
Biosynthesis of Polyketides in Heterologous Hosts.
B. A. Pfeifer and C. Khosla (2001)
Microbiol. Mol. Biol. Rev. 65, 106-118
   Abstract »    Full Text »    PDF »
Comparative Genetic Analysis of Mycobacterium ulcerans and Mycobacterium marinum Reveals Evidence of Recent Divergence.
T. P. Stinear, G. A. Jenkin, P. D. R. Johnson, and J. K. Davies (2000)
J. Bacteriol. 182, 6322-6330
   Abstract »    Full Text »
Necrosis of Lung Epithelial Cells during Infection with Mycobacterium tuberculosis Is Preceded by Cell Permeation.
K. M. Dobos, E. A. Spotts, F. D. Quinn, and C. H. King (2000)
Infect. Immun. 68, 6300-6310
   Abstract »    Full Text »    PDF »
Biochemical and Genetic Evidence for Phospholipase C Activity in Mycobacterium ulcerans.
A. Gomez, A. Mve-Obiang, B. Vray, J. Remacle, K. Chemlal, W. M. Meyers, F. Portaels, and P.-A. Fonteyne (2000)
Infect. Immun. 68, 2995-2997
   Abstract »    Full Text »    PDF »
A Mycobacterium ulcerans Toxin, Mycolactone, Causes Apoptosis in Guinea Pig Ulcers and Tissue Culture Cells.
K. M. George, L. Pascopella, D. M. Welty, and P. L. C. Small (2000)
Infect. Immun. 68, 877-883
   Abstract »    Full Text »    PDF »
The Inhibitory Action of Mycobacterium ulcerans Soluble Factor on Monocyte/T Cell Cytokine Production and NF-{kappa}B Function.
A. A. Pahlevan, D. J. M. Wright, C. Andrews, K. M. George, P. L. C. Small, and B. M. Foxwell (1999)
J. Immunol. 163, 3928-3935
   Abstract »    Full Text »    PDF »
Identification of Mycobacterium tuberculosis RNAs synthesized in response to phagocytosis by human macrophages by selective capture of transcribed sequences (SCOTS).
J. E. Graham and J. E. Clark-Curtiss (1999)
PNAS 96, 11554-11559
   Abstract »    Full Text »    PDF »
Molecular Epidemiologic Evaluation of Transmissibility and Virulence of Mycobacterium tuberculosis.
J. T. Rhee, A. S. Piatek, P. M. Small, L. M. Harris, S. V. Chaparro, F. R. Kramer, and D. Alland (1999)
J. Clin. Microbiol. 37, 1764-1770
   Abstract »    Full Text »
Biochemical Characterization of Acyl Carrier Protein (AcpM) and Malonyl-CoA:AcpM Transacylase (mtFabD), Two Major Components of Mycobacterium tuberculosis Fatty Acid Synthase II.
L. Kremer, K. M. Nampoothiri, S. Lesjean, L. G. Dover, S. Graham, J. Betts, P. J. Brennan, D. E. Minnikin, C. Locht, and G. S. Besra (2001)
J. Biol. Chem. 276, 27967-27974
   Abstract »    Full Text »    PDF »
Diethyl Phthalate, a Chemotactic Factor Secreted by Helicobacter pylori.
D. A. Keire, P. Anton, K. F. Faull, E. Ruth, J. H. Walsh, P. Chew, D. Quisimoro, M. Territo, and J. R. Reeve Jr. (2001)
J. Biol. Chem. 276, 48847-48853
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)