scholarly journals Mechanism of Mycolactone Toxin Membrane Permeation: Atomistic vs Coarse-Grained MARTINI Simulations

2018 ◽  
Author(s):  
F. Aydin ◽  
R. Sun ◽  
J. M. J. Swanson
Keyword(s):  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Coarse Grained ◽  
Membrane Permeation ◽  
Lipid Trafficking ◽  
Ulcer Disease ◽  
Cellular Processes ◽  
Coarse Grained Simulations ◽  
Dynamics Simulations

ABSTRACTMycolactone, a cytotoxic and immunosuppressive macrolide produced by Mycobacterium ulcerans, is the central virulent factor in the skin disease Buruli ulcer. This multifunctional cytotoxin affects fundamental cellular processes such as cell adhesion, immune response and cell death by targeting various cellular structures. Developing effective diagnostics that target mycolactone has been challenging, potentially due to suspected interactions with lipophilic architectures, including membranes. To better understand the pathogenesis of Buruli ulcer disease, aid in the development of diagnostics, and learn how amphiphiles in general use lipid trafficking to navigate the host environment, we seek to understand the nature of mycolactone-membrane interactions. Herein we characterize how the two dominant isomers of mycolactone (A and B) interact with and permeate DPPC membranes with all-atom molecular dynamics simulations employing transition tempered metadynamics, and compare these results with those obtained by MARTINI coarse-grained simulations. Our all-atom simulations reveal that both isomers have a strong preference to associate with the membrane, although their mechanisms and energetics of membrane permeation differ slightly. Water molecules are found to play an important role in the permeation process. Although the MARTINI coarse-grained simulations give the correct free energy of membrane association, they fail to capture the mechanism of permeation and role of water during permeation as seen in all-atom simulations.

scholarly journals Recent advances: role of mycolactone in the pathogenesis and monitoring of Mycobacterium ulcerans infection/Buruli ulcer disease

2015 ◽  
Vol 18 (1) ◽  
pp. 17-29 ◽  
Author(s):  
Fred Stephen Sarfo ◽  
Richard Phillips ◽  
Mark Wansbrough‐Jones ◽  
Rachel E. Simmonds
Keyword(s):  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Ulcer Disease ◽  
Recent Advances

scholarly journals Molecular Mechanisms Underpinning the Circulation and Cellular Uptake of Mycobacterium ulcerans Toxin Mycolactone

2021 ◽  
Vol 12 ◽  
Author(s):  
Bruno Tello Rubio ◽  
Florence Bugault ◽  
Blandine Baudon ◽  
Bertrand Raynal ◽  
Sébastien Brûlé ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Molecular Mechanisms ◽  
Scavenger Receptor ◽  
Buruli Ulcer ◽  
Systemic Circulation ◽  
Mycobacterium Ulcerans ◽  
Host Cells ◽  
Ulcer Disease ◽  
Major Mechanism ◽  
Specific Association

Mycolactone is a diffusible lipid toxin produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer disease. Altough bacterially derived mycolactone has been shown to traffic from cutaneous foci of infection to the bloodstream, the mechanisms underpinning its access to systemic circulation and import by host cells remain largely unknown. Using biophysical and cell-based approaches, we demonstrate that mycolactone specific association to serum albumin and lipoproteins is necessary for its solubilization and is a major mechanism to regulate its bioavailability. We also demonstrate that Scavenger Receptor (SR)-B1 contributes to the cellular uptake of mycolactone. Overall, we suggest a new mechanism of transport and cell entry, challenging the dogma that the toxin enters host cells via passive diffusion.

scholarly journals Aquatic Snails, Passive Hosts of Mycobacterium ulcerans

2004 ◽  
Vol 70 (10) ◽  
pp. 6296-6298 ◽  
Author(s):  
Laurent Marsollier ◽  
Tchibozo Sévérin ◽  
Jacques Aubry ◽  
Richard W. Merritt ◽  
Jean-Paul Saint André ◽  
...  
Keyword(s):  
Buruli Ulcer ◽  
Indirect Evidence ◽  
Mycobacterium Ulcerans ◽  
Aquatic Environments ◽  
Potential Vector ◽  
Ulcer Disease ◽  
Skin Ulcers ◽  
Chronic Skin ◽  
Favorable Conditions ◽  
Water Bugs

ABSTRACT Accumulative indirect evidence of the epidemiology of Mycobacterium ulcerans infections causing chronic skin ulcers (i.e., Buruli ulcer disease) suggests that the development of this pathogen and its transmission to humans are related predominantly to aquatic environments. We report that snails could transitorily harbor M. ulcerans without offering favorable conditions for its growth and replication. A novel intermediate link in the transmission chain of M. ulcerans becomes likely with predator aquatic insects in addition to phytophage insects. Water bugs, such as Naucoris cimicoides, a potential vector of M. ulcerans, were shown to be infected specifically by this bacterium after feeding on snails experimentally exposed to M. ulcerans.

scholarly journals Modelling lipid systems in fluid with Lattice Boltzmann Molecular Dynamics simulations and hydrodynamics

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Astrid F. Brandner ◽  
Stepan Timr ◽  
Simone Melchionna ◽  
Philippe Derreumaux ◽  
Marc Baaden ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Lattice Boltzmann ◽  
Coarse Grained ◽  
Implicit Solvent ◽  
Mesoscopic Scale ◽  
Coarse Grained Model ◽  
Dynamics Simulations ◽  
Cellular Compartments ◽  
Biological Entities

Abstract In this work we present the coupling between Dry Martini, an efficient implicit solvent coarse-grained model for lipids, and the Lattice Boltzmann Molecular Dynamics (LBMD) simulation technique in order to include naturally hydrodynamic interactions in implicit solvent simulations of lipid systems. After validating the implementation of the model, we explored several systems where the action of a perturbing fluid plays an important role. Namely, we investigated the role of an external shear flow on the dynamics of a vesicle, the dynamics of substrate release under shear, and inquired the dynamics of proteins and substrates confined inside the core of a vesicle. Our methodology enables future exploration of a large variety of biological entities and processes involving lipid systems at the mesoscopic scale where hydrodynamics plays an essential role, e.g. by modulating the migration of proteins in the proximity of membranes, the dynamics of vesicle-based drug delivery systems, or, more generally, the behaviour of proteins in cellular compartments.

Associations Between Mycobacterium ulcerans and Aquatic Plant Communities of West Africa: Implications for Buruli Ulcer Disease

EcoHealth ◽  
2014 ◽  
Vol 11 (2) ◽  
pp. 184-196 ◽  
Author(s):  
Mollie McIntosh ◽  
Heather Williamson ◽  
M. Eric Benbow ◽  
Ryan Kimbirauskas ◽  
Charles Quaye ◽  
...  
Keyword(s):  
West Africa ◽  
Plant Communities ◽  
Aquatic Plant ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Ulcer Disease

scholarly journals Molecular characterization of Mycobacterium ulcerans DNA gyrase and identification of mutations reduced susceptibility against quinolones in vitro

2021 ◽  
Author(s):  
Hyun Kim ◽  
Shigtarou Mori ◽  
Tsuyoshi Kenri ◽  
Yasuhiko Suzuki
Keyword(s):  
Buruli Ulcer ◽  
Dna Gyrase ◽  
Resistance Mechanisms ◽  
Docking Studies ◽  
Mycobacterium Ulcerans ◽  
Amino Acid Residues ◽  
Wild Type Enzyme ◽  
Ulcer Disease

ABSTRACTBuruli ulcer disease is a neglected necrotizing and disabling cutaneous tropical illness caused by Mycobacterium ulcerans (Mul). Fluoroquinolone (FQ), used in the treatment of this disease, has been known to act by inhibiting the enzymatic activities of DNA gyrase; however, the detailed molecular basis of these characteristics and the FQ resistance mechanisms in Mul remains unknown. This study investigated the detailed molecular mechanism of Mul DNA gyrase and the contribution of FQ resistance in vitro using recombinant proteins from the Mul subsp. shinshuense and Agy99 strains with reduced sensitivity to FQs. The IC50 of FQs against Ala91Vla and Asp95Gly mutants of Mul shinshuense and Agy99 GyrA subunits were 3.7- to 42.0-fold higher than those against wild-type enzyme. Similarly, the CC25 was 10- to 210-fold higher than those for the WT enzyme. Furthermore, the interaction between the amino acid residues of WT/mutant Mul DNA gyrase and FQ side chains was assessed via molecular docking studies. This is the first detailed study showing the contribution of Mul DNA GyrA subunit mutations to reduce the susceptibility against FQs.

scholarly journals Molecular dynamics simulations of membrane deformation induced by the amphiphilic helices of Epsin, Sar1p and Arf1

2017 ◽  
Author(s):  
Zhen-lu Li
Keyword(s):  
Lipid Membranes ◽  
Critical Role ◽  
Membrane Curvature ◽  
Coarse Grained ◽  
Insertion Depth ◽  
Membrane Deformation ◽  
Specific Distribution ◽  
Amphiphilic Helix ◽  
Coarse Grained Simulations ◽  
Dynamics Simulations

AbstractThe N-terminal amphiphilic helices of proteins Epsin, Sar1p and Arf1 play a critical role in initiating membrane deformation. We present here the study of the interactions of these amphiphilic helices with the lipid membranes by combining the all-atom and coarse-grained simulations. In the all-atom simulations, we find that the amphiphilic helices of Epsin and Sar1p have a shallower insertion depth into the membrane compared to the amphiphilic helix of Arf1, but remarkably, the amphiphilic helices of Epsin and Sar1p induce higher asymmetry in the lipid packing between the two monolayers of the membrane. The insertion depth of amphiphilic helix into the membrane is determined not only by the overall hydrophobicity but also by the specific distribution of polar and non-polar residues along the helix. To directly compare their ability of deforming the membrane, we further apply coarse-grained simulations to investigate the membranes deformation under the insertion of multiple helices. Importantly, it is found that the amphiphilic helices of Epsin and Sar1p generate a larger membrane curvature than that of Arf1, in accord with the experimental results qualitatively. These findings enhance our understanding of the molecular mechanism of the protein-driven membrane remodeling.

scholarly journals Mycolactone toxin induces an inflammatory response by targeting the IL-1β pathway: Mechanistic insight into Buruli ulcer pathophysiology

2020 ◽  
Vol 16 (12) ◽  
pp. e1009107
Author(s):  
M. Foulon ◽  
M. Robbe-Saule ◽  
J. Manry ◽  
L. Esnault ◽  
Y. Boucaud ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Inflammatory Factors ◽  
Dependent Manner ◽  
Local Inflammatory Response ◽  
Mechanistic Insight ◽  
Insight Into

Mycolactone, a lipid-like toxin, is the major virulence factor of Mycobacterium ulcerans, the etiological agent of Buruli ulcer. Its involvement in lesion development has been widely described in early stages of the disease, through its cytotoxic and immunosuppressive activities, but less is known about later stages. Here, we revisit the role of mycolactone in disease outcome and provide the first demonstration of the pro-inflammatory potential of this toxin. We found that the mycolactone-containing mycobacterial extracellular vesicles produced by M. ulcerans induced the production of IL-1β, a potent pro-inflammatory cytokine, in a TLR2-dependent manner, targeting NLRP3/1 inflammasomes. We show our data to be relevant in a physiological context. The in vivo injection of these mycolactone-containing vesicles induced a strong local inflammatory response and tissue damage, which were prevented by corticosteroids. Finally, several soluble pro-inflammatory factors, including IL-1β, were detected in infected tissues from mice and Buruli ulcer patients. Our results revisit Buruli ulcer pathophysiology by providing new insight, thus paving the way for the development of new therapeutic strategies taking the pro-inflammatory potential of mycolactone into account.

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