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The Pseudomonas aeruginosa outer membrane permeability barrier and how to overcome it
Abstract:
The intrinsic resistance of P. aeruginosa to most hydrophilic antibiotics can be explained, in part, on the basis of its low outer membrane permeability. Protein F which constitutes the major outer membrane porin protein for the uptake of hydrophilic compounds, is poorly functional. We have demonstrated that less than 1% of the 200,000 or so copies of protein F per cell can form active functional channels. Our working hypothesis is that the species of LPS associated with individual protein F trimers determines whether these trimers adopt a functional conformation. Since low outer membrane permeability constitutes a major problem for the penetration of antibiotics into P. aeruginosa, we have started to search for compounds which permeabilize outer membranes ('permeabilizers') and thus would be potentially synergistic with antibiotics. Eighteen permeabilizer compounds have been discovered and fall into defined chemical groupings including polycations, organic cations and divalent cation chelators.
Insights
Pseudomonas aeruginosa exhibits intrinsic antibiotic resistance due to low outer membrane permeability. Researchers identified 18 novel permeabilizer compounds that enhance antibiotic effectiveness by increasing this permeability.
Area of Science:
- Microbiology
- Biochemistry
- Drug Discovery
Background:
- Pseudomonas aeruginosa displays intrinsic resistance to hydrophilic antibiotics, largely due to its low outer membrane permeability.
- The primary hydrophilic compound uptake channel, Protein F, is poorly functional, with less than 1% of cellular copies forming active channels.
Purpose of the Study:
- To investigate the hypothesis that lipopolysaccharide (LPS) species associated with Protein F trimers influence their functional conformation.
- To identify compounds that increase outer membrane permeability (permeabilizers) to enhance antibiotic efficacy against P. aeruginosa.
Main Methods:
- Investigated the functional state of Protein F in P. aeruginosa outer membranes.
- Screened for compounds that permeabilize the bacterial outer membrane.
- Classified discovered permeabilizers into chemical groups.
Main Results:
- Confirmed that a small fraction of Protein F trimers are functional, suggesting a regulatory mechanism.
- Discovered 18 novel permeabilizer compounds.
- Identified permeabilizers belonging to chemical classes such as polycations, organic cations, and divalent cation chelators.
Conclusions:
- Outer membrane permeability is a critical factor in P. aeruginosa's antibiotic resistance.
- Permeabilizer compounds show potential for synergistic activity with antibiotics, overcoming resistance mechanisms.
- The identified permeabilizers offer new avenues for developing combination therapies against P. aeruginosa infections.