Can membrane composition traffic toxins? Mycolactone and preferential membrane interactions

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biology

Background:

• Mycolactone is a cytotoxic macrolide produced by Mycobacterium ulcerans, causing Buruli ulcer.
• Its amphiphilic nature suggests membrane interactions are key to its pathogenicity, but specifics remain unknown.
• Understanding mycolactone-membrane interactions could aid in developing diagnostics for Buruli ulcer.

Purpose of the Study:

• To characterize mycolactone's association with and permeation through endoplasmic reticulum (ER) and plasma membranes (PMs).
• To elucidate the role of membrane properties in mycolactone's cellular localization and pathogenicity.

Main Methods:

• Molecular dynamics simulations.
• Enhanced free-energy sampling techniques.
• Modeling of mammalian ER and PMs.

Main Results:

• Mycolactone exhibits different permeation mechanisms in ER versus PM models.
• Increased membrane order in PMs influences toxin permeation.
• ER membrane interactions are energetically favorable for mycolactone due to hydration, deformation, and lipid tail preferences.
• Lipid packing disruption destabilizes mycolactone in PMs.

Conclusions:

• Mycolactone's localization is driven by specific interactions with the ER membrane.
• Membrane biophysical properties dictate mycolactone's cellular entry and distribution.
• These findings provide a basis for understanding Buruli ulcer pathogenesis and developing targeted diagnostics.