ArticleProceedings of the National Academy of Sciences of the United States of America2004
Giant plasmid-encoded polyketide synthases produce the macrolide toxin of Mycobacterium ulcerans.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 165 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
165 citing papers in PubMed, 1 synthesis or guideline pooled it, 380 citations in OpenAlex.
- Ecology and transmission of Buruli ulcer disease: a systematic review.PLoS neglected tropical diseases · 2010Pooled it
- Aberrant stromal tissue factor localisation and mycolactone-driven vascular dysfunction, exacerbated by IL-1β, are linked to fibrin formation in Buruli ulcer lesions.PLoS pathogens · 2022Trial
- Developing the protein quality control system inSynthetic and systems biotechnology · 2026Article
- Giant linear plasmids in Mycobacterium avium harbour a tRNA array unit.DNA research : an international journal for rapid publication of reports on genes and genomes · 2026Article
- Buruli ulcer.Nature reviews. Disease primers · 2025Review
- Successful treatment with joint retention of Mycobacterium ulcerans prosthetic joint infection in a patient with rheumatoid arthritis.PLoS neglected tropical diseases · 2025Article
- Expanding catalytic versatility of modular polyketide synthases for alcohol biosynthesis.Nature chemical biology · 2025Article
- One-step loop-mediated isothermal amplification system forMicrobiology spectrum · 2025Article
- Improving polyketide biosynthesis by rescuing the translation of truncated mRNAs into functional polyketide synthase subunits.Nature communications · 2025Article
- Review
- Systematic review: Global host range, case fatality and detection rates ofJournal of clinical tuberculosis and other mycobacterial diseases · 2024Review
- Module-Based Polyketide Synthase Engineering forACS synthetic biology · 2023Review
- Inflammasome-triggered IL-18 controls skin inflammation in the progression of Buruli ulcer.PLoS pathogens · 2023Article
- ProfilingFuture science OA · 2023Review
- Comparative Evaluation of LAMP and Nested PCR for the Rapid Diagnosis ofInfection and drug resistance · 2023Article
- Article
- Protective Efficacy of BCG Vaccine againstVaccines · 2022Review
- Overview: Mycobacterium ulcerans Disease (Buruli Ulcer).Methods in molecular biology (Clifton, N.J.) · 2022Article
- Analysis of key genes inFrontiers in tropical diseases · 2022Article
- Overview: Mycolactone , the Macrolide Toxin of Mycobacterium ulcerans.Methods in molecular biology (Clifton, N.J.) · 2022Article
105 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 1 institution in 2 countries.
Funding
Abstract
Mycobacterium ulcerans (MU), an emerging human pathogen harbored by aquatic insects, is the causative agent of Buruli ulcer, a devastating skin disease rife throughout Central and West Africa. Mycolactone, an unusual macrolide with cytotoxic and immunosuppressive properties, is responsible for the massive s.c. tissue destruction seen in Buruli ulcer. Here, we show that MU contains a 174-kb plasmid, pMUM001, bearing a cluster of genes encoding giant polyketide synthases (PKSs), and polyketide-modifying enzymes, and demonstrate that these are necessary and sufficient for mycolactone synthesis. This is a previously uncharacterized example of plasmid-mediated virulence in a Mycobacterium, and the emergence of MU as a pathogen most likely reflects the acquisition of pMUM001 by horizontal transfer. The 12-membered core of mycolactone is produced by two giant, modular PKSs, MLSA1 (1.8 MDa) and MLSA2 (0.26 MDa), whereas its side chain is synthesized by MLSB (1.2 MDa), a third modular PKS highly related to MLSA1. There is an extreme level of sequence identity within the different domains of the MLS cluster (>97% amino acid identity), so much so that the 16 ketosynthase domains seem functionally identical. This is a finding of significant consequence for our understanding of polyketide biochemistry. Such detailed knowledge of mycolactone will further the investigation of its mode of action and the development of urgently needed therapeutic strategies to combat Buruli ulcer.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.