The Chemistry and Biology of Mycolactones

Overview

Journal Beilstein J Org Chem

Specialty Chemistry

Date 2017 Sep 15

PMID 28904608

Citations 17

Authors

Matthias Gehringer

Karl-Heinz Altmann

Affiliations

Soon will be listed here.

Abstract

Mycolactones are a group of macrolides excreted by the human pathogen , which exhibit cytotoxic, immunosuppressive and analgesic properties. As the virulence factor of , mycolactones are central to the pathogenesis of the neglected disease Buruli ulcer, a chronic and debilitating medical condition characterized by necrotic skin ulcers. Due to their complex structure and fascinating biology, mycolactones have inspired various total synthesis endeavors and structure-activity relationship studies. Although this review intends to cover all synthesis efforts in the field, special emphasis is given to the comparison of conceptually different approaches and to the discussion of more recent contributions. Furthermore, a detailed discussion of molecular targets and structure-activity relationships is provided.

Citing Articles

Genomic insights into the plasmidome of non-tuberculous mycobacteria.

Diricks M, Maurer F, Dreyer V, Barilar I, Utpatel C, Merker M Genome Med. 2025; 17(1):19.

PMID: 40038805 PMC: 11877719. DOI: 10.1186/s13073-025-01443-7.

Exploring Mycolactone-The Unique Causative Toxin of Buruli Ulcer: Biosynthetic, Synthetic Pathways, Biomarker for Diagnosis, and Therapeutic Potential.

Akolgo G, Asiedu K, Amewu R Toxins (Basel). 2024; 16(12.

PMID: 39728786 PMC: 11678992. DOI: 10.3390/toxins16120528.

Mycolactone A vs. B: Multiscale Simulations Reveal the Roles of Localization and Association in Isomer-Specific Toxicity.

Nguyen J, da Hora G, Swanson J Toxins (Basel). 2023; 15(8).

PMID: 37624243 PMC: 10467071. DOI: 10.3390/toxins15080486.

From Bacterial Toxin to Therapeutic Agent: The Unexpected Fate of Mycolactone.

Ricci D, Demangel C Toxins (Basel). 2023; 15(6).

PMID: 37368670 PMC: 10303314. DOI: 10.3390/toxins15060369.

Sec61 blockade therapy overrides resistance to proteasome inhibitors and immunomodulatory drugs in multiple myeloma.

Domenger A, Ricci D, Mayau V, Majlessi L, Marcireau C, Dadaglio G Front Oncol. 2023; 13:1110916.

PMID: 36776330 PMC: 9911829. DOI: 10.3389/fonc.2023.1110916.

References

Guerinot A, Reymond S, Cossy J . Iron-catalyzed cross-coupling of alkyl halides with alkenyl grignard reagents. Angew Chem Int Ed Engl. 2007; 46(34):6521-4. DOI: 10.1002/anie.200702206. View

Namba K, Cui S, Wang J, Kishi Y . A new method for translating the asymmetric Ni/Cr-mediated coupling reactions from stoichiometric to catalytic. Org Lett. 2005; 7(24):5417-9. DOI: 10.1021/ol052084s. View

Tornoe C, Christensen C, Meldal M . Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J Org Chem. 2002; 67(9):3057-64. DOI: 10.1021/jo011148j. View

Cadapan L, Arslanian R, Carney J, Zavala S, Small P, Licari P . Suspension cultivation of Mycobacterium ulcerans for the production of mycolactones. FEMS Microbiol Lett. 2001; 205(2):385-9. DOI: 10.1111/j.1574-6968.2001.tb10977.x. View

Willson S, Kaufman M, Merritt R, Williamson H, Malakauskas D, Benbow M . Fish and amphibians as potential reservoirs of Mycobacterium ulcerans, the causative agent of Buruli ulcer disease. Infect Ecol Epidemiol. 2013; 3. PMC: 3580280. DOI: 10.3402/iee.v3i0.19946. View

Babu V, Zhou Y, Kishi Y . Design, synthesis, and cytotoxicity of stabilized mycolactone analogs. Bioorg Med Chem Lett. 2017; 27(5):1274-1277. DOI: 10.1016/j.bmcl.2017.01.036. View

Merritt R, Walker E, Small P, Wallace J, Johnson P, Benbow M . Ecology and transmission of Buruli ulcer disease: a systematic review. PLoS Negl Trop Dis. 2010; 4(12):e911. PMC: 3001905. DOI: 10.1371/journal.pntd.0000911. View

Kapuscinski J . DAPI: a DNA-specific fluorescent probe. Biotech Histochem. 1995; 70(5):220-33. DOI: 10.3109/10520299509108199. View

Goto M, Nakanaga K, Aung T, Hamada T, Yamada N, Nomoto M . Nerve damage in Mycobacterium ulcerans-infected mice: probable cause of painlessness in buruli ulcer. Am J Pathol. 2006; 168(3):805-11. PMC: 1606540. DOI: 10.2353/ajpath.2006.050375. View

10.

Wu Y, Tan H, Shui G, Bauvy C, Huang Q, Wenk M . Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem. 2010; 285(14):10850-61. PMC: 2856291. DOI: 10.1074/jbc.M109.080796. View

11.

Laplante M, Sabatini D . mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93. PMC: 3331679. DOI: 10.1016/j.cell.2012.03.017. View

12.

Sarfo F, Phillips R, Wansbrough-Jones M, Simmonds R . Recent advances: role of mycolactone in the pathogenesis and monitoring of Mycobacterium ulcerans infection/Buruli ulcer disease. Cell Microbiol. 2015; 18(1):17-29. PMC: 4705457. DOI: 10.1111/cmi.12547. View

13.

Burgos C, Canales E, Matos K, Soderquist J . Asymmetric allyl- and crotylboration with the robust, versatile, and recyclable 10-TMS-9-borabicyclo[3.3.2]decanes. J Am Chem Soc. 2005; 127(22):8044-9. DOI: 10.1021/ja043612i. View

14.

Cernijenko A, Risgaard R, Baran P . 11-Step Total Synthesis of (-)-Maoecrystal V. J Am Chem Soc. 2016; 138(30):9425-8. PMC: 4974602. DOI: 10.1021/jacs.6b06623. View

15.

Timmermans P, Wong P, Chiu A, Herblin W, Benfield P, Carini D . Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev. 1993; 45(2):205-51. View

16.

Igarashi M, Strittmatter S, Vartanian T, Fishman M . Mediation by G proteins of signals that cause collapse of growth cones. Science. 1993; 259(5091):77-9. DOI: 10.1126/science.8418498. View

17.

FENNER F, Leach R . Studies on Mycobacterium ulcerans. I. Serological relationship to other mycobacteria. Aust J Exp Biol Med Sci. 1952; 30(1):1-10. DOI: 10.1038/icb.1952.1. View

18.

George K, Pascopella L, WELTY D, Small P . A Mycobacterium ulcerans toxin, mycolactone, causes apoptosis in guinea pig ulcers and tissue culture cells. Infect Immun. 2000; 68(2):877-83. PMC: 97217. DOI: 10.1128/IAI.68.2.877-883.2000. View

19.

Gersbach P, Jantsch A, Feyen F, Scherr N, Dangy J, Pluschke G . A ring-closing metathesis (RCM)-based approach to mycolactones A/B. Chemistry. 2011; 17(46):13017-31. DOI: 10.1002/chem.201101799. View

20.

Wymann M, Arcaro A . Platelet-derived growth factor-induced phosphatidylinositol 3-kinase activation mediates actin rearrangements in fibroblasts. Biochem J. 1994; 298 Pt 3:517-20. PMC: 1137889. DOI: 10.1042/bj2980517. View