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

Dennapa Saeloh, Varomyalin Tipmanee, Kin Ki Jim, Marien P. Dekker, Wilbert Bitter, Supayang P. Voravuthikunchai, Michaela Wenzel*, Leendert W. Hamoen

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Article numbere1006876
JournalPlos Pathogens
Volume14
Issue number2
DOIs
Publication statusPublished - 16 Feb 2018

Funding

This work was funded by an NWO STW-Vici grant (#12128 to LWH, https://www.nwo.nl/en) and TRF Senior Research Scholar grant by the Thailand Research Fund (RTA5880005 to SPV, www.trf.or.th/eng/). DS was funded by the Higher Education Research Promotion and National Research University Project of Thailand, Office of Higher Education Commission Ph.D. Scholarship, and a scholarship for an overseas thesis research study from the Graduate School, Prince of Songkla University. Electron microscopy was performed at the VU/VUmc EM facility, supported by the Netherlands Organization for Scientific Research (NWO, middelgroot 91111009). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. We thank Urša Gubenšek and Terrens N. V. Saaki (University of Amsterdam) for constructing strains UG-10 and TNVS30D, Tjalling Siersma (University of Amsterdam) for assistance with MICs, Norbert O. Vischer (University of Amsterdam) and Henrik Strahl (Newcastle University) for writing the ImageJ ‘Calculate GP’ plugin, Marina Rautenbach (Stellenbosch University) for supplying gramicidin S, and Nils Metzler-Nolte (Ruhr University Bochum) for supplying MP196. Lipid analysis was performed at the Laboratory for Genetic Metabolic Diseases, Academic Medical Center Amsterdam. We gratefully acknowledge TEM support from Jan R. T. van Weering (VU University).

FundersFunder number
Nederlandse Organisatie voor Wetenschappelijk Onderzoek12128
Thailand Research FundRTA5880005

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