Total Syntheses of Mycolactone A/B and its Analogues for the Exploration of the Biology of Buruli Ulcer

Saint-Auret, Sarah; Chany, Anne‐Caroline; Casarotto, Virginie; Tresse, Cédric; L, Parmentier; Abdelkafi, Hajer; Blanchard, Nicolas

doi:10.2533/chimia.2017.836

Cited by 9 publications

(8 citation statements)

References 26 publications

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“…68 However, the low yields and complexity of chemical schemes for mycolactone synthesis make its large-scale production for clinical applications challenging. 45,110,111 Structure-activity relationship studies showed that the mycolactone subunit corresponding to lactone core and southern polyketide chain is critical for binding to Sec61 and biological activity. 68,73,112 While less potent than natural mycolactone, the truncated version retained capacity to block cytokine production by neutrophils, macrophages, and lymphocytes in vitro.…”

Section: Ther Apeuti Cp Otentialof Mycol Ac Tonementioning

confidence: 99%

“…Using mouse models, we showed that systematically delivered mycolactone confers protection against chronic skin inflammation, rheumatoid arthritis, and inflammatory pain 68 . However, the low yields and complexity of chemical schemes for mycolactone synthesis make its large‐scale production for clinical applications challenging 45,110,111 . Structure‐activity relationship studies showed that the mycolactone subunit corresponding to lactone core and southern polyketide chain is critical for binding to Sec61 and biological activity 68,73,112 .…”

Section: Therapeutic Potential Of Mycolactonementioning

confidence: 99%

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Immunity against Mycobacterium ulcerans: The subversive role of mycolactone

Demangel

2021

Immunological Reviews

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Section: Ther Apeuti Cp Otentialof Mycol Ac Tonementioning

confidence: 99%

Section: Therapeutic Potential Of Mycolactonementioning

confidence: 99%

Immunity against Mycobacterium ulcerans: The subversive role of mycolactone

Demangel

2021

Immunological Reviews

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“…The biosynthesis of mycolactone is permitted by giant polyketide synthases, whose genes are harboured by a megaplasmid [Stinear et al., ]. M. ulcerans strains of different geographical origins, or genetically related mycobacteria, produce variants of a canonical mycolactone structure, corresponding to a 12‐membered lactone ring substituted with two polyketide‐derived chains [Figure ; reviewed in Gehringer and Altmann, ; Saint‐Auret et al., ]. Mycolactone is central to the pathogenesis of BU.…”

Section: Buruli Ulcer the Third Most Common Mycobacterial Diseasementioning

confidence: 99%

Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease

Demangel

High

2018

Biology of the Cell

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Infection with Mycobacterium ulcerans results in a necrotising skin disease known as a Buruli ulcer, the pathology of which is directly linked to the bacterial production of the toxin mycolactone. Recent studies have identified the protein translocation machinery of the endoplasmic reticulum (ER) membrane as the primary cellular target of mycolactone, and shown that the toxin binds to the core subunit of the Sec61 complex. Mycolactone binding strongly inhibits the capacity of the Sec61 translocon to transport newly synthesised membrane and secretory proteins into and across the ER membrane. Since the ER acts as the entry point for the mammalian secretory pathway, and hence regulates initial access to the entire endomembrane system, mycolactone-treated cells have a reduced ability to produce a range of proteins including secretory cytokines and plasma membrane receptors. The global effect of this molecular blockade of protein translocation at the ER is that the host is unable to mount an effective immune response to the underlying mycobacterial infection. Prolonged exposure to mycolactone is normally cytotoxic, since it triggers stress responses activating the transcription factor ATF4 and ultimately inducing apoptosis.

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“…Total chemical synthesis of mycolactone has provided a means for obtaining robust, homogenous, well-defined samples with high reproducibility [17,21,22,31,32]. However, total synthesis of mycolactone is an extremely complicated process and requires substantial synthetic expertise, thus limiting the global supply of this crucial material [18,19,33].…”

Section: Introductionmentioning

confidence: 99%

Understanding the Significance of Biochemistry in the Storage, Handling, Purification, and Sampling of Amphiphilic Mycolactone

Kubicek-Sutherland

Anderson

et al. 2019

Toxins

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Mycolactone, the amphiphilic macrolide toxin secreted by Mycobacterium ulcerans, plays a significant role in the pathology and manifestations of Buruli ulcer (BU). Consequently, it follows that the toxin is a suitable target for the development of diagnostics and therapeutics for this disease. Yet, several challenges have deterred such development. For one, the lipophilic nature of the toxin makes it difficult to handle and store and contributes to variability associated with laboratory experimentation and purification yields. In this manuscript, we have attempted to incorporate our understanding of the lipophilicity of mycolactone in order to define the optimal methods for the storage, handling, and purification of this toxin. We present a systematic correlation of variability associated with measurement techniques (thin-layer chromatography (TLC), mass spectrometry (MS), and UV-Vis spectrometry), storage conditions, choice of solvents, as well as the impact of each of these on toxin function as assessed by cellular cytotoxicity. We also compared natural mycolactone extracted from bacterial culture with synthesized toxins in laboratory (solvents, buffers) and physiologically relevant (serum) matrices. Our results point to the greater stability of mycolactone in organic, as well as detergent-containing, solvents, regardless of the container material (plastic, glass, or silanized tubes). They also highlight the presence of toxin in samples that may be undetectable by any one technique, suggesting that each detection approach captures different configurations of the molecule with varying specificity and sensitivity. Most importantly, our results demonstrate for the very first time that amphiphilic mycolactone associates with host lipoproteins in serum, and that this association will likely impact our ability to study, diagnose, and treat Buruli ulcers in patients.

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Total Syntheses of Mycolactone A/B and its Analogues for the Exploration of the Biology of Buruli Ulcer

Cited by 9 publications

References 26 publications

Immunity against Mycobacterium ulcerans: The subversive role of mycolactone

Immunity against Mycobacterium ulcerans: The subversive role of mycolactone

Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease

Understanding the Significance of Biochemistry in the Storage, Handling, Purification, and Sampling of Amphiphilic Mycolactone

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