History, biology and chemistry of Mycobacterium ulcerans infections (Buruli ulcer disease).

Mycobacterium ulcerans infections (Buruli ulcer disease) have a long history that can be traced back 150 years. The successive discoveries of the mycobacteria in 1948 and of mycolactone A/B in 1999, the toxin responsible for this dramatic necrotic skin disease, resulted in a paradigm shift concerning the disease itself and in a broader sense, delineated an entirely new role for bioactive polyketides as virulence factors. The fascinating history, biology and chemistry of M. ulcerans infections are discussed in this review.

[1]  Jun Li,et al.  Structure-Activity Relationship Studies on the Macrolide Exotoxin Mycolactone of Mycobacterium ulcerans , 2013, PLoS neglected tropical diseases.

[2]  F. Portaels,et al.  Buruli ulcer (Mycobacterium ulcerans infection): a re-emerging disease. , 2009 .

[3]  Mercy J. Newman,et al.  Secondary Bacterial Infections of Buruli Ulcer Lesions Before and After Chemotherapy with Streptomycin and Rifampicin , 2013, PLoS neglected tropical diseases.

[4]  B. Foxwell,et al.  The inhibitory action of Mycobacterium ulcerans soluble factor on monocyte/T cell cytokine production and NF-kappa B function. , 1999, Journal of immunology.

[5]  Erin E. Carlson,et al.  Natural products as chemical probes. , 2010, ACS chemical biology.

[6]  S. Cole,et al.  Buruli ulcer: reductive evolution enhances pathogenicity of Mycobacterium ulcerans , 2009, Nature Reviews Microbiology.

[7]  Pierre Legras,et al.  Impact of Mycobacterium ulcerans Biofilm on Transmissibility to Ecological Niches and Buruli Ulcer Pathogenesis , 2007, PLoS pathogens.

[8]  J. L. La Clair,et al.  Synthetic studies on the mycolactone core. , 2010, Organic & biomolecular chemistry.

[9]  R. W. Hoffmann Natural product synthesis: changes over time. , 2013, Angewandte Chemie.

[10]  J. Pedrosa,et al.  Evidence for an Intramacrophage Growth Phase of Mycobacterium ulcerans , 2006, Infection and Immunity.

[11]  Koen Peeters Grietens,et al.  Correction: “It Is Me Who Endures but My Family That Suffers”: Social Isolation as a Consequence of the Household Cost Burden of Buruli Ulcer Free of Charge Hospital Treatment , 2008, PLoS Neglected Tropical Diseases.

[12]  Harry Johnston The Nile quest, a record of the exploration of the Nile and its basin , 1903 .

[13]  Hui Hong,et al.  Identification using LC-MSn of co-metabolites in the biosynthesis of the polyketide toxin mycolactone by a clinical isolate of Mycobacterium ulcerans. , 2003, Chemical communications.

[14]  H. Sissons,et al.  A new mycobacterial infection in man. , 1948, The Journal of pathology and bacteriology.

[15]  Timothy L. Foley,et al.  The unusual macrocycle forming thioesterase of mycolactone. , 2008, Molecular bioSystems.

[16]  K. Asiedu,et al.  Buruli Ulcer in Ghana: Results of a National Case Search , 2002, Emerging infectious diseases.

[17]  L. Marsollier,et al.  Aquatic Plants Stimulate the Growth of and Biofilm Formation by Mycobacterium ulcerans in Axenic Culture and Harbor These Bacteria in the Environment , 2004, Applied and Environmental Microbiology.

[18]  B. Nay,et al.  Hirsutellones and beyond: figuring out the biological and synthetic logics toward chemical complexity in fungal PKS-NRPS compounds. , 2013, Natural product reports.

[19]  則久 石井,et al.  ブルーリ潰瘍(Mycobacterium ulcerans感染症)の神経傷害におけるmycolactoneの役割 , 2007 .

[20]  A. Jantsch,et al.  A ring-closing metathesis (RCM)-based approach to mycolactones A/B. , 2011, Chemistry.

[21]  P. Rácz,et al.  A stepwise approach to the laboratory diagnosis of Buruli ulcer disease , 2006, Tropical medicine & international health : TM & IH.

[22]  J. L. La Clair,et al.  Synthesis of the mycolactone core by ring-closing metathesis. , 2006, Chemical communications.

[23]  G. Bretzel,et al.  Implementation of a National Reference Laboratory for Buruli Ulcer Disease in Togo , 2013, PLoS neglected tropical diseases.

[24]  S. Cole,et al.  Functional analysis and annotation of the virulence plasmid pMUM001 from Mycobacterium ulcerans. , 2005, Microbiology.

[25]  Hui Hong,et al.  Deciphering the genetic basis for polyketide variation among mycobacteria producing mycolactones , 2008, BMC Genomics.

[26]  C. Robinson,et al.  Microbiological, Histological, Immunological, and Toxin Response to Antibiotic Treatment in the Mouse Model of Mycobacterium ulcerans Disease , 2013, PLoS neglected tropical diseases.

[27]  Marion Leclerc,et al.  Mycolactone Diffuses from Mycobacterium ulcerans–Infected Tissues and Targets Mononuclear Cells in Peripheral Blood and Lymphoid Organs , 2008, PLoS neglected tropical diseases.

[28]  A. Kemp,et al.  Acquired T-helper 1 lymphocyte anergy following infection with Mycobacterium ulcerans. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[29]  M. Benbow,et al.  Fish and amphibians as potential reservoirs of Mycobacterium ulcerans, the causative agent of Buruli ulcer disease , 2013, Infection ecology & epidemiology.

[30]  Robert L. White,et al.  Gas-phase hydrolysis of phenyl acetate and phenyl benzoate by superoxide ion , 1983 .

[31]  Hui Hong,et al.  The Cell Wall-Associated Mycolactone Polyketide Synthases Are Necessary but Not Sufficient for Mycolactone Biosynthesis , 2013, PloS one.

[32]  P. de Rijk,et al.  Direct detection and identification of Mycobacterium ulcerans in clinical specimens by PCR and oligonucleotide-specific capture plate hybridization , 1997, Journal of clinical microbiology.

[33]  W. Meyers,et al.  Immunosuppressive properties of the soluble toxin from Mycobacterium ulcerans. , 1988, The Journal of infectious diseases.

[34]  A. Kemp,et al.  Cytokine Profiles of Patients Infected with Mycobacterium ulcerans and Unaffected Household Contacts , 2002, Infection and Immunity.

[35]  A. Fürstner,et al.  Efficient Total Syntheses of Resin Glycosides and Analogues by Ring-Closing Olefin Metathesis , 1999 .

[36]  W. Hockmeyer,et al.  Toxin of Mycobacterium ulcerans. Production and effects in guinea pig skin. , 1974, Archives of dermatology.

[37]  W. T. van der Graaf,et al.  Beliefs and attitudes toward Buruli ulcer in Ghana. , 2002, The American journal of tropical medicine and hygiene.

[38]  D. Hopwood,et al.  Genetic Contributions to Understanding Polyketide Synthases. , 1997, Chemical reviews.

[39]  Xiaolei Wang,et al.  Asymmetric Total Synthesis of (−)‐Cladospolide B , 2008 .

[40]  D. Connor,et al.  BURULI (MYCOBACTERIAL) ULCERATION IN UGANDA. (A NEW FOCUS OF BURULI ULCER IN MADI DISTRICT, UGANDA): REPORT OF A FIELD STUDY. , 1965, East African medical journal.

[41]  Y. Mizui,et al.  Total synthesis of the potent antitumor macrolides pladienolide B and D. , 2007, Angewandte Chemie.

[42]  A. Fürstner,et al.  Macrocycles by Ring-Closing Metathesis , 1997 .

[43]  Sarojini Adusumilli,et al.  Structure determination of mycolactone C via total synthesis. , 2004, Organic letters.

[44]  A. Colorni,et al.  Evolution of Mycobacterium ulcerans and Other Mycolactone-Producing Mycobacteria from a Common Mycobacterium marinum Progenitor , 2006, Journal of bacteriology.

[45]  Y. Kishi,et al.  Photochemistry of mycolactone A/B, the causative toxin of Buruli ulcer. , 2012, Journal of the American Chemical Society.

[46]  H. Brown,et al.  Chiral synthesis via organoboranes. 27. Remarkably rapid and exceptionally enantioselective (approaching 100% ee) allylboration of representative aldehydes at -100.degree. under new, salt-free conditions , 1991 .

[47]  G. Pluschke,et al.  Diagnosis of Mycobacterium ulcerans infection (Buruli ulcer) at a treatment centre in Ghana: a retrospective analysis of laboratory results of clinically diagnosed cases , 2008, Tropical medicine & international health : TM & IH.

[48]  Paul D. R. Johnson,et al.  Subtractive Hybridization Reveals a Type I Polyketide Synthase Locus Specific to Mycobacterium ulcerans , 2003, Journal of bacteriology.

[49]  Julian Parkhill,et al.  Insights from the complete genome sequence of Mycobacterium marinum on the evolution of Mycobacterium tuberculosis. , 2008, Genome research.

[50]  K. Dooley,et al.  Activities of Rifampin, Rifapentine and Clarithromycin Alone and in Combination against Mycobacterium ulcerans Disease in Mice , 2011, PLoS neglected tropical diseases.

[51]  G. Pluschke,et al.  Large Sequence Polymorphisms Unveil the Phylogenetic Relationship of Environmental and Pathogenic Mycobacteria Related to Mycobacterium ulcerans , 2009, Applied and Environmental Microbiology.

[52]  Torsten Seemann,et al.  Complete Genome Sequence of the Frog Pathogen Mycobacterium ulcerans Ecovar Liflandii , 2012, Journal of bacteriology.

[53]  F. Portaels,et al.  Biochemical and Genetic Evidence for Phospholipase C Activity in Mycobacterium ulcerans , 2000, Infection and Immunity.

[54]  H. Leirs,et al.  Terrestrial Small Mammals as Reservoirs of Mycobacterium ulcerans in Benin , 2010, Applied and Environmental Microbiology.

[55]  P. Leadlay,et al.  Organization of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus: analysis of the enzymatic domains in the modular polyketide synthase. , 1996, Gene.

[56]  G. Pluschke,et al.  Systemic suppression of interferon‐γ responses in Buruli ulcer patients resolves after surgical excision of the lesions caused by the extracellular pathogen Mycobacterium ulcerans , 2006, Journal of leukocyte biology.

[57]  K. Asiedu,et al.  Socioeconomic implications of Buruli ulcer in Ghana: a three-year review. , 1998, The American journal of tropical medicine and hygiene.

[58]  Patrick J. Brennan,et al.  Characterization of Novel Macrolide Toxins, Mycolactones A and B, from a Human Pathogen, Mycobacterium ulcerans , 1999 .

[59]  G. Pluschke,et al.  Secondary Buruli Ulcer Skin Lesions Emerging Several Months after Completion of Chemotherapy: Paradoxical Reaction or Evidence for Immune Protection? , 2011, PLoS neglected tropical diseases.

[60]  E. Negishi,et al.  Stereoselective synthesis of the side chains of mycolactones A and B featuring stepwise double substitutions of 1,1-dibromo-1-alkenes. , 2006, Angewandte Chemie.

[61]  Stefan Wetzel,et al.  Natural-product-derived fragments for fragment-based ligand discovery , 2012, Nature Chemistry.

[62]  F. Koehn,et al.  The evolving role of natural products in drug discovery , 2005, Nature Reviews Drug Discovery.

[63]  Hui Hong,et al.  Common Evolutionary Origin for the Unstable Virulence Plasmid pMUM Found in Geographically Diverse Strains of Mycobacterium ulcerans , 2005, Journal of bacteriology.

[64]  P. Small,et al.  Stereochemistry of the core structure of the mycolactones. , 2001, Journal of the American Chemical Society.

[65]  Emmanuelle Perret,et al.  Modulation of the host immune response by a transient intracellular stage of Mycobacterium ulcerans: the contribution of endogenous mycolactone toxin , 2005, Cellular microbiology.

[66]  P. Leadlay,et al.  Molecular basis of Celmer's rules: stereochemistry of catalysis by isolated ketoreductase domains from modular polyketide synthases. , 2005, Chemistry & biology.

[67]  J. Hayman,et al.  Consensus recommendations for the diagnosis, treatment and control of Mycobacterium ulcerans infection (Bairnsdale or Buruli ulcer) in Victoria, Australia , 2007, The Medical journal of Australia.

[68]  F. Sarfo,et al.  Clinical Efficacy of Combination of Rifampin and Streptomycin for Treatment of Mycobacterium ulcerans Disease , 2010, Antimicrobial Agents and Chemotherapy.

[69]  D. Chatterjee,et al.  Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence. , 1999, Science.

[70]  F. Portaels,et al.  BCG vaccine effectiveness against Buruli ulcer: a case-control study in Benin. , 2006, The American journal of tropical medicine and hygiene.

[71]  Angelo Martino,et al.  Selective suppression of dendritic cell functions by Mycobacterium ulcerans toxin mycolactone , 2007, The Journal of experimental medicine.

[72]  F. Portaels,et al.  Buruli Ulcer: A Review of In Vitro Tests to Screen Natural Products for Activity against Mycobacterium ulcerans , 2011, Planta medica.

[73]  J. Hayman Mycobacterium ulcerans infection , 1991, The Lancet.

[74]  R. Phillips,et al.  Buruli ulcer: emerging from obscurity , 2006, The Lancet.

[75]  Timothy P. Stinear,et al.  Mycobacterium ulcerans in Mosquitoes Captured during Outbreak of Buruli Ulcer, Southeastern Australia , 2007, Emerging infectious diseases.

[76]  P. Bouchard,et al.  Mycobacterium ulcerans infections cause progressive muscle atrophy and dysfunction, and mycolactone impairs satellite cell proliferation. , 2011, American journal of physiology. Regulatory, integrative and comparative physiology.

[77]  J. Clancey MYCOBACTERIAL SKIN ULCERS IN UGANDA: DESCRIPTION OF A NEW MYCOBACTERIUM (MYCOBACTERIUM BURULI). , 1964, The Journal of pathology and bacteriology.

[78]  C. Horsfield,et al.  Efficacy of the Combination Rifampin-Streptomycin in Preventing Growth of Mycobacterium ulcerans in Early Lesions of Buruli Ulcer in Humans , 2005, Antimicrobial Agents and Chemotherapy.

[79]  G. Pluschke,et al.  The genome, evolution and diversity of Mycobacterium ulcerans. , 2012, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[80]  K. Handasyde,et al.  A Major Role for Mammals in the Ecology of Mycobacterium ulcerans , 2010, PLoS neglected tropical diseases.

[81]  G. Evano,et al.  Copper-Mediated Cross-Coupling Reactions , 2013 .

[82]  Alexander Deiters,et al.  Synthesis of oxygen- and nitrogen-containing heterocycles by ring-closing metathesis. , 2004, Chemical reviews.

[83]  Sarojini Adusumilli,et al.  Mycolactone-Mediated Inhibition of Tumor Necrosis Factor Production by Macrophages Infected with Mycobacterium ulcerans Has Implications for the Control of Infection , 2007, Infection and Immunity.

[84]  M. Monaghan,et al.  A Molecular Approach to Identifying the Natural Prey of the African Creeping Water Bug Naucoris, A Potential Reservoir of Mycobacterium ulcerans , 2012, Journal of insect science.

[85]  D. Boakye,et al.  A quick and cost effective method for the diagnosis of Mycobacterium ulcerans infection , 2012, BMC Infectious Diseases.

[86]  J. Fyfe,et al.  Risk of Buruli Ulcer and Detection of Mycobacterium ulcerans in Mosquitoes in Southeastern Australia , 2011, PLoS neglected tropical diseases.

[87]  K. Rottner,et al.  Role of the WASP family proteins for Mycobacterium marinum actin tail formation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[88]  A. Colorni,et al.  Strain Variation in Mycobacteriummarinum Fish Isolates , 2002, Applied and Environmental Microbiology.

[89]  J. Grosset,et al.  Promising Clinical Efficacy of Streptomycin-Rifampin Combination for Treatment of Buruli Ulcer (Mycobacterium ulcerans Disease) , 2007, Antimicrobial Agents and Chemotherapy.

[90]  S. Gillespie,et al.  A paradigm for the molecular identification of Mycobacterium species in a routine diagnostic laboratory. , 2007, Journal of medical microbiology.

[91]  L. Marsollier,et al.  Photodegradation of the Mycobacterium ulcerans Toxin, Mycolactones: Considerations for Handling and Storage , 2012, PloS one.

[92]  Y. Amoako,et al.  Detection of Viable Mycobacterium ulcerans in Clinical Samples by a Novel Combined 16S rRNA Reverse Transcriptase/IS2404 Real-Time qPCR Assay , 2012, PLoS neglected tropical diseases.

[93]  L. Marsollier,et al.  Aquatic Insects as a Vector for Mycobacterium ulcerans , 2002, Applied and Environmental Microbiology.

[94]  Hui Hong,et al.  Mycolactone Gene Expression Is Controlled by Strong SigA-Like Promoters with Utility in Studies of Mycobacterium ulcerans and Buruli Ulcer , 2009, PLoS neglected tropical diseases.

[95]  J. Porco,et al.  Synthesis of the Tetracyclic Core of the Tetrapetalones through Transannular Oxidative [4+3] Cyclization , 2005 .

[96]  C. D. da Luz,et al.  The Use of Polliniferous Resources by Melipona capixaba, an Endangered Stingless Bee Species , 2012, Journal of insect science.

[97]  Sarojini Adusumilli,et al.  Globally Distributed Mycobacterial Fish Pathogens Produce a Novel Plasmid-Encoded Toxic Macrolide, Mycolactone F , 2006, Infection and Immunity.

[98]  Y. Kazumi,et al.  Synthesis and structure of two new mycolactones isolated from M. ulcerans subsp. shinshuense. , 2012, Organic Letters.

[99]  Y. Hoshino,et al.  Laboratory procedures for the detection and identification of cutaneous non‐tuberculous mycobacterial infections , 2013, The Journal of dermatology.

[100]  Y. Kishi,et al.  Total synthesis and stereochemistry of mycolactone F. , 2008, Journal of the American Chemical Society.

[101]  Margarida Saraiva,et al.  Mycobacterium ulcerans Triggers T-Cell Immunity followed by Local and Regional but Not Systemic Immunosuppression , 2010, Infection and Immunity.

[102]  M. Boissinot,et al.  Subcutaneous injection of Mycobacterium ulcerans causes necrosis, chronic inflammatory response and fibrosis in skeletal muscle. , 2008, Microbes and infection.

[103]  P. Dijkstra,et al.  Assessment of functional limitations caused by Mycobacterium ulcerans infection: towards a Buruli Ulcer Functional Limitation Score , 2003, Tropical medicine & international health : TM & IH.

[104]  P. Rácz,et al.  Dry reagent-based polymerase chain reaction compared with other laboratory methods available for the diagnosis of Buruli ulcer disease. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[105]  D. Campbell,et al.  Immune Response to Infection withMycobacterium ulcerans , 2001, Infection and Immunity.

[106]  Sarojini Adusumilli,et al.  Giant plasmid-encoded polyketide synthases produce the macrolide toxin of Mycobacterium ulcerans. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[107]  Matthew L Albert,et al.  Immunosuppressive signature of cutaneous Mycobacterium ulcerans infection in the peripheral blood of patients with buruli ulcer disease. , 2009, The Journal of infectious diseases.

[108]  M. Benbow,et al.  Interaction of Mycobacterium ulcerans with Mosquito Species: Implications for Transmission and Trophic Relationships , 2010, Applied and Environmental Microbiology.

[109]  G. Evano,et al.  Copper-mediated coupling reactions and their applications in natural products and designed biomolecules synthesis. , 2008, Chemical reviews.

[110]  Jeung-Hoon Lee,et al.  Innate immune responses to Mycobacterium ulcerans via toll‐like receptors and dectin‐1 in human keratinocytes , 2009, Cellular microbiology.

[111]  Stefan Wetzel,et al.  Charting, navigating, and populating natural product chemical space for drug discovery. , 2012, Journal of medicinal chemistry.

[112]  W. Hockmeyer,et al.  Further characterization of Mycobacterium ulcerans toxin , 1978, Infection and immunity.

[113]  T. Sata,et al.  Detection of Mycobacterium ulcerans by the Loop Mediated Isothermal Amplification Method , 2012, PLoS neglected tropical diseases.

[114]  Wenjun Li,et al.  Scalable and efficient synthesis of the mycolactone core. , 2010, Tetrahedron.

[115]  Leonard Katz,et al.  Manipulation of Modular Polyketide Synthases. , 1997, Chemical reviews.

[116]  Matthew D. Ronsheim,et al.  Ring expansions of beta-keto lactones with zinc carbenoids: syntheses of (+)-patulolide A and (+/-)-patulolide B. , 2003, The Journal of organic chemistry.

[117]  A. Barnaud,et al.  Genetic Diversity and Population Structure of Mycobacterium marinum: New Insights into Host and Environmental Specificities , 2012, Journal of Clinical Microbiology.

[118]  E. Negishi,et al.  Highly stereoselective total synthesis of fully hydroxy-protected mycolactones A and B and their stereoisomerization upon deprotection. , 2011, Chemistry.

[119]  J. Staunton,et al.  Polyketide biosynthesis: a millennium review. , 2001, Natural product reports.

[120]  C. Hertweck,et al.  The biosynthetic logic of polyketide diversity. , 2009, Angewandte Chemie.

[121]  Georges Bismuth,et al.  Mycolactone impairs T cell homing by suppressing microRNA control of L-selectin expression , 2011, Proceedings of the National Academy of Sciences.

[122]  G. Pluschke,et al.  Differential Gene Repertoire in Mycobacterium ulcerans Identifies Candidate Genes for Patho-Adaptation , 2008, PLoS neglected tropical diseases.

[123]  A New Role for Polyketides. , 2000, Angewandte Chemie.

[124]  F. Portaels,et al.  Mycobacterium ulcerans infection: control, diagnosis, and treatment. , 2006, The Lancet. Infectious diseases.

[125]  Y. Chooi,et al.  Navigating the fungal polyketide chemical space: from genes to molecules. , 2012, The Journal of organic chemistry.

[126]  G. Pluschke,et al.  Combining PCR with microscopy to reduce costs of laboratory diagnosis of Buruli ulcer. , 2011, The American journal of tropical medicine and hygiene.

[127]  Y. Kishi,et al.  Highly sensitive, operationally simple, cost/time effective detection of the mycolactones from the human pathogen Mycobacterium ulcerans. , 2010, Chemical communications.

[128]  M. Goto,et al.  Mycolactone Is Responsible for the Painlessness of Mycobacterium ulcerans Infection (Buruli Ulcer) in a Murine Study , 2008, Infection and Immunity.

[129]  Mahavir Singh,et al.  Buruli ulcer disease: prospects for a vaccine , 2009, Medical Microbiology and Immunology.

[130]  Hui Hong,et al.  Mycolactones: immunosuppressive and cytotoxic polyketides produced by aquatic mycobacteria , 2008, Natural product reports.

[131]  Pascal Lenormand,et al.  Mycolactone Diffuses into the Peripheral Blood of Buruli Ulcer Patients - Implications for Diagnosis and Disease Monitoring , 2011, PLoS neglected tropical diseases.

[132]  U. Certa,et al.  Evolution of two distinct phylogenetic lineages of the emerging human pathogen Mycobacterium ulcerans , 2007, BMC Evolutionary Biology.

[133]  P. Butcher,et al.  Cytokine mRNA Expression in Mycobacteriam ulcerans-Infected Human Skin and Correlation with Local Inflammatory Response , 2006, Infection and Immunity.

[134]  A. Radford What's in a name? Ulcerans disease: infections due to Mycobacterium ulcerans. , 2009, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[135]  Sylvain Aubry,et al.  Synthesis and structure assignment of the minor metabolite arising from the frog pathogen Mycobacterium liflandii. , 2010, Tetrahedron letters.

[136]  K. Dobos,et al.  Mycobacterium ulcerans Cytotoxicity in an Adipose Cell Model , 2001, Infection and Immunity.

[137]  Georges Bismuth,et al.  Mycolactone Suppresses T Cell Responsiveness by Altering Both Early Signaling and Posttranslational Events , 2009, The Journal of Immunology.

[138]  F. Portaels,et al.  Heterogeneity of Mycolactones Produced by Clinical Isolates of Mycobacterium ulcerans: Implications for Virulence , 2003, Infection and Immunity.

[139]  F. Portaels,et al.  Mycobacterium bovis BCG Vaccination as Prophylaxis against Mycobacterium ulcerans Osteomyelitis in Buruli Ulcer Disease , 2004, Infection and Immunity.

[140]  B. Ross,et al.  Development of a PCR assay for rapid diagnosis of Mycobacterium ulcerans infection , 1997, Journal of clinical microbiology.

[141]  Yoshito Kishi,et al.  Chemistry of mycolactones, the causative toxins of Buruli ulcer , 2011, Proceedings of the National Academy of Sciences.

[142]  J. Fyfe,et al.  Mycobacterium ulcerans and Other Mycolactone-Producing Mycobacteria Should Be Considered a Single Species , 2010, PLoS neglected tropical diseases.

[143]  F. Fenner THE SIGNIFICANCE OF THE INCUBATION PERIOD IN INFECTIOUS DISEASES , 1950, The Medical journal of Australia.

[144]  J. Pedrosa,et al.  Cellular Immunity Confers Transient Protection in Experimental Buruli Ulcer following BCG or Mycolactone-Negative Mycobacterium ulcerans Vaccination , 2012, PloS one.

[145]  G. Pluschke,et al.  Local activation of the innate immune system in Buruli ulcer lesions. , 2007, The Journal of investigative dermatology.

[146]  Kenneth D. Doig,et al.  On the origin of Mycobacterium ulcerans, the causative agent of Buruli ulcer , 2012, BMC Genomics.

[147]  D. Boakye,et al.  Potential Role for Fish in Transmission of Mycobacterium ulcerans Disease (Buruli Ulcer): an Environmental Study , 2004, Applied and Environmental Microbiology.

[148]  P. Small,et al.  Complete structure of the mycolactones. , 2001, Journal of the American Chemical Society.

[149]  P. Small,et al.  Partial Purification and Characterization of Biological Effects of a Lipid Toxin Produced byMycobacterium ulcerans , 1998, Infection and Immunity.

[150]  C. Côté,et al.  Limited repair and structural damages displayed by skeletal muscles loaded with mycolactone. , 2009, Microbes and infection.

[151]  S. Cole,et al.  Comprehensive proteome analysis of Mycobacterium ulcerans and quantitative comparison of mycolactone biosynthesis , 2008, Proteomics.

[152]  M. Ståhle,et al.  Antioxidants Protect Keratinocytes against M. ulcerans Mycolactone Cytotoxicity , 2010, PloS one.

[153]  S. Guadagnini,et al.  Colonization of the salivary glands of Naucoris cimicoides by Mycobacterium ulcerans requires host plasmatocytes and a macrolide toxin, mycolactone , 2005, Cellular microbiology.

[154]  E. Walker,et al.  Ecology and Transmission of Buruli Ulcer Disease: A Systematic Review , 2010, PLoS neglected tropical diseases.

[155]  F. Alcaide,et al.  Current treatment of nontuberculous mycobacteriosis: an update , 2012, Expert opinion on pharmacotherapy.

[156]  J. Frenette,et al.  Investigation of wild-type and mycolactone-negative mutant Mycobacterium ulcerans on skeletal muscle: IGF-1 protects against mycolactone-induced muscle catabolism. , 2013, American journal of physiology. Regulatory, integrative and comparative physiology.

[157]  E. Carreira,et al.  Probing the biology of natural products: molecular editing by diverted total synthesis. , 2010, Angewandte Chemie.

[158]  M. Ucko,et al.  Mycobacterium marinum Infections in Fish and Humans in Israel , 2005, Journal of Clinical Microbiology.

[159]  K. Weissman,et al.  Ketoreduction in Mycolactone Biosynthesis: Insight into Substrate Specificity and Stereocontrol from Studies of Discrete Ketoreductase Domains in vitro , 2006, Chembiochem : a European journal of chemical biology.

[160]  Mark Welch,et al.  Genetic approaches to polyketide antibiotics. 1. , 2005, Chemical reviews.

[161]  L. Mosi,et al.  Heterogeneity in the stereochemistry of mycolactones isolated from M. marinum: toxins produced by fresh vs. saltwater fish pathogens. , 2009, Chemical communications.

[162]  C. Townsend Buruli toxin genes decoded. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[163]  S. Ostroff,et al.  Emergence of Buruli ulcer disease in the Daloa region of Cote d'Ivoire. , 1995, The American journal of tropical medicine and hygiene.

[164]  D. Alsop The Bairnsdale Ulcer. , 1972, The Australian and New Zealand journal of surgery.

[165]  F. Sarfo,et al.  Detection of Mycolactone A/B in Mycobacterium ulcerans–Infected Human Tissue , 2010, PLoS neglected tropical diseases.

[166]  Y. Barogui,et al.  Healthcare seeking behaviour for Buruli ulcer in Benin: a model to capture therapy choice of patients and healthy community members. , 2008, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[167]  G. Pluschke,et al.  Independent Loss of Immunogenic Proteins in Mycobacterium ulcerans Suggests Immune Evasion , 2008, Clinical and Vaccine Immunology.

[168]  C. Demangel,et al.  A diverted total synthesis of mycolactone analogues: an insight into Buruli ulcer toxins. , 2011, Chemistry.

[169]  J. Wallace,et al.  Persistent Association of Mycobacterium ulcerans with West African Predaceous Insects of the Family Belostomatidae , 2008, Applied and Environmental Microbiology.

[170]  T. Grammer,et al.  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 , 2005, Infection and Immunity.

[171]  P. Small,et al.  Uptake and cellular actions of mycolactone, a virulence determinant for Mycobacterium ulcerans. , 2003, Microbial pathogenesis.

[172]  A. Longatto-Filho,et al.  Phage Therapy Is Effective against Infection by Mycobacterium ulcerans in a Murine Footpad Model , 2013, PLoS neglected tropical diseases.

[173]  B. Ross,et al.  Identification and Characterization of IS2404 and IS2606: Two Distinct Repeated Sequences for Detection of Mycobacterium ulcerans by PCR , 1999, Journal of Clinical Microbiology.

[174]  H. Boezen,et al.  Cytokine Responses to Stimulation of Whole Blood from Patients with Buruli Ulcer Disease in Ghana , 2005, Clinical Diagnostic Laboratory Immunology.

[175]  Hui Hong,et al.  A Novel Mycolactone Toxin Obtained by Biosynthetic Engineering , 2007, Chembiochem : a European journal of chemical biology.

[176]  F. Portaels,et al.  Therapeutic itineraries of patients with ulcerated forms of Mycobacterium ulcerans (Buruli ulcer) disease in a rural health zone in the Democratic Republic of Congo , 2009, Tropical medicine & international health : TM & IH.

[177]  P. Rácz,et al.  Comparative study of the sensitivity of different diagnostic methods for the laboratory diagnosis of Buruli ulcer disease. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[178]  K. Nicolaou The emergence of the structure of the molecule and the art of its synthesis. , 2013, Angewandte Chemie.

[179]  J. Hayman,et al.  Mycobacterium ulcerans infection: an eponymous ulcer , 2007 .

[180]  J. Cottin,et al.  Oral treatment for Mycobacterium ulcerans infection: results from a pilot study in Benin. , 2011, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[181]  Patrick Caffrey,et al.  Conserved Amino Acid Residues Correlating With Ketoreductase Stereospecificity in Modular Polyketide Synthases , 2003, Chembiochem : a European journal of chemical biology.

[182]  S. Baldwin,et al.  Stereoselective synthesis of (.+-.) methyl nonactate , 1987 .

[183]  J. Cossy,et al.  Iron-catalyzed cross-coupling of alkyl halides with alkenyl grignard reagents. , 2007, Angewandte Chemie.

[184]  Koichi Suzuki,et al.  Buruli ulcer and current situation in Japan: A new emerging cutaneous Mycobacterium infection , 2012, The Journal of dermatology.

[185]  J. Carney,et al.  Suspension cultivation of Mycobacterium ulcerans for the production of mycolactones. , 2001, FEMS microbiology letters.

[186]  A. Renzaho,et al.  Community‐based study on knowledge, attitude and practice on the mode of transmission, prevention and treatment of the Buruli ulcer in Ga West District, Ghana , 2007, Tropical medicine & international health : TM & IH.

[187]  J. Parkhill,et al.  Reductive evolution and niche adaptation inferred from the genome of Mycobacterium ulcerans, the causative agent of Buruli ulcer. , 2007, Genome research.

[188]  Joan Muela Ribera,et al.  What Role Do Traditional Beliefs Play in Treatment Seeking and Delay for Buruli Ulcer Disease?–Insights from a Mixed Methods Study in Cameroon , 2012, PloS one.

[189]  A. Radford Mycobacterium ulcerans in Australia. , 1975, Australian and New Zealand journal of medicine.

[190]  M. Khokha,et al.  Characterization of a Mycobacterium ulcerans-like infection in a colony of African tropical clawed frogs (Xenopus tropicalis). , 2004, Comparative medicine.

[191]  Cécile Uwizeye,et al.  Fine-Needle Aspiration, an Efficient Sampling Technique for Bacteriological Diagnosis of Nonulcerative Buruli Ulcer , 2009, Journal of Clinical Microbiology.

[192]  P. de Rijk,et al.  Variability in 3' end of 16S rRNA sequence of Mycobacterium ulcerans is related to geographic origin of isolates , 1996, Journal of clinical microbiology.

[193]  Marie-France Carlier,et al.  Mycolactone activation of Wiskott-Aldrich syndrome proteins underpins Buruli ulcer formation. , 2013, The Journal of clinical investigation.

[194]  P. Small,et al.  A Mycobacterium ulcerans Toxin, Mycolactone, Causes Apoptosis in Guinea Pig Ulcers and Tissue Culture Cells , 2000, Infection and Immunity.

[195]  P. Launois,et al.  Differential Production of Systemic and Intralesional Gamma Interferon and Interleukin-10 in Nodular and Ulcerative Forms of Buruli Disease , 2004, Infection and Immunity.

[196]  O. Dodge,et al.  Mycobacterial skin ulcers in Uganda. , 1961, Lancet.

[197]  M. Goto,et al.  Nerve damage in Mycobacterium ulcerans-infected mice: probable cause of painlessness in buruli ulcer. , 2006, The American journal of pathology.

[198]  Enrico Colombo,et al.  A Mycobacterium ulcerans toxin, mycolactone, induces apoptosis in primary human keratinocytes and in HaCaT cells. , 2010, Microbes and infection.

[199]  W. Meyers,et al.  Cytotoxic Activity of Mycobacterium ulcerans , 1974, Infection and immunity.

[200]  G. Maw,et al.  Scope of the chromium(II)-mediated synthesis of E-alkenylstannanes from aldehydes and Bu3SnCHBr2 , 1995 .

[201]  Paul D. R. Johnson,et al.  Comparative Genetic Analysis of Mycobacterium ulcerans and Mycobacterium marinum Reveals Evidence of Recent Divergence , 2000, Journal of bacteriology.

[202]  M. Fischbach,et al.  Assembly-line enzymology for polyketide and nonribosomal Peptide antibiotics: logic, machinery, and mechanisms. , 2006, Chemical reviews.

[203]  Weihong Qi,et al.  Genomic Diversity and Evolution of Mycobacterium ulcerans Revealed by Next-Generation Sequencing , 2009, PLoS pathogens.

[204]  R. W. Hoffmann,et al.  Allylic 1,3-strain as a controlling factor in stereoselective transformations , 1989 .

[205]  Sarojini Adusumilli,et al.  Mycobacterium ulcerans toxic macrolide, mycolactone modulates the host immune response and cellular location of M. ulcerans in vitro and in vivo , 2005, Cellular microbiology.

[206]  J. Grosset,et al.  BCG-Mediated Protection against Mycobacterium ulcerans Infection in the Mouse , 2011, PLoS neglected tropical diseases.

[207]  G. O'Doherty,et al.  An enantioselective synthesis of benzylidene-protected syn-3,5-dihydroxy carboxylate esters via osmium, palladium, and base catalysis. , 2001, Organic letters.