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.
Highlights
The vast majority of antibiotics currently used in the clinic are derived from microbial sources [1]
Bacterial antibiotic resistance constitutes a major public healthcare issue and deaths caused by antimicrobial resistance are expected to soon exceed the number of cancerrelated fatalities
In order to fight resistance, new antibiotics have to be developed that are not affected by existing microbial resistance strategies
Summary
The vast majority of antibiotics currently used in the clinic are derived from microbial sources [1]. Considering the alarming rise in antibiotic-resistant pathogens, it is crucial to explore the potential of antimicrobials from herbal sources for new antibiotic development [3,4] One such promising compound is the acylphloroglucinol rhodomyrtone, isolated from the leaves of the rose myrtle Rhodomyrtus tomentosa [5]. Rhodomyrtone did not cause skin irritation upon topical application in rabbits [10] and acute toxicity tests did not show adverse effects in mice, when injected [11] It has been proven effective against Propionibacterium acne biofilms [10,12], showed excellent results in preventing staphylococcal adhesion and invasion in a tissue model of bovine mastitis [13], and prevented adhesion of dental pathogens to plastic surfaces and human buccal cells [14]
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