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PLoS Pathog. 2018 Feb 16;14(2):e1006876. doi: 10.1371/journal.ppat.1006876. eCollection 2018 Feb.

The novel antibiotic rhodomyrtone traps membrane proteins in vesicles with increased fluidity.

Author information

1
Excellence Research Laboratory on Natural Products, Faculty of Science and Natural Product Research Center of Excellence, Prince of Songkla University, Hat Yai, Songkhla, Thailand.
2
Department of Microbiology, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla, Thailand.
3
Department of Biomedical Sciences, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand.
4
Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands.
5
Department of Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Neuroscience Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
6
Department of Molecular Cell Biology, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
7
Bacterial Cell Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.

Abstract

The acylphloroglucinol rhodomyrtone is a promising new antibiotic isolated from the rose myrtle Rhodomyrtus tomentosa, a plant used in Asian traditional medicine. While many studies have demonstrated its antibacterial potential in a variety of clinical applications, very little is known about the mechanism of action of rhodomyrtone. Preceding studies have been focused on intracellular targets, but no specific intracellular protein could be confirmed as main target. Using live cell, high-resolution, and electron microscopy we demonstrate that rhodomyrtone causes large membrane invaginations with a dramatic increase in fluidity, which attract a broad range of membrane proteins. Invaginations then form intracellular vesicles, thereby trapping these proteins. Aberrant protein localization impairs several cellular functions, including the respiratory chain and the ATP synthase complex. Being uncharged and devoid of a particular amphipathic structure, rhodomyrtone did not seem to be a typical membrane-inserting molecule. In fact, molecular dynamics simulations showed that instead of inserting into the bilayer, rhodomyrtone transiently binds to phospholipid head groups and causes distortion of lipid packing, providing explanations for membrane fluidization and induction of membrane curvature. Both its transient binding mode and its ability to form protein-trapping membrane vesicles are unique, making it an attractive new antibiotic candidate with a novel mechanism of action.

PMID:
29451901
PMCID:
PMC5833292
DOI:
10.1371/journal.ppat.1006876
[Indexed for MEDLINE]
Free PMC Article

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