Can a membrane protein nanotrap inactivate multidrug efflux pumps?

Research Project, 2022 – 2024

Rhodomyrtone is a natural acylphloroglucinol compound that is produced by the rose myrtle Rhodomyrtus tomentosa. Native to southern and southeastern Asia, this healing plant is commonly applied in traditional Asian medicine for its antibacterial and anti-inflammatory properties. The active compound rhodomyrtone has a unique mechanism, by which it kills bacteria: it acts as a membrane protein nanotrap. The antibiotic binds to the bacterial cell membrane and creates hyper-fluid regions, which attract a range of membrane proteins. These regions are more flexible than normal membranes and can easily bend. Rhodomyrtone forces these flexible regions inwards and thereby creates membrane vesicles of 50 nm average diameter, effectively trapping the attracted membrane proteins. This leads to simultaneous inhibition of a range of cellular functions resulting in very low resistance rates.

This mechanism opens up fundamentally new possibilities for innovative antibacterial treatments and promotes the key hypothesis that the protein-trapping mechanism of rhodomyrtone could disable multi-drug efflux pumps. These membrane-bound transport proteins are a crucial antibiotic resistance mechanism that renders many common antibiotics completely ineffective.

The permeability barrier constituted by the cell membrane and the antibiotic efflux pumps residing in the same are two of the most powerful antibiotic resistance mechanisms in baceria. The unprecedented protein-trapping mechanism of rhodomyrtone offers a unique possibility to bypass both resistance mechanisms and has the potential to unravel a never seen before strategy to combat highly drug-resistant bacteria.