Fosfomycin Permeation through the Outer Membrane Porin OmpF

Area of Science:

• Microbiology
• Biophysics
• Computational Biology

Background:

• Fosfomycin is a crucial antibiotic for treating urinary tract infections.
• Its mechanism involves inhibiting peptidoglycan synthesis by targeting the MurA enzyme.
• However, fosfomycin's passage through the Gram-negative bacterial outer membrane remains poorly understood.

Purpose of the Study:

• To investigate the permeability of fosfomycin across the Gram-negative bacterial outer membrane.
• To elucidate the molecular mechanisms of fosfomycin translocation through porins.
• To provide insights into the transport of phosphonic acid antibiotics.

Main Methods:

• Electrophysiology experiments, including zero-current assays.
• All-atom molecular dynamics simulations.
• Free-energy calculations and applied-field techniques.

Main Results:

• Fosfomycin rapidly permeates the abundant Escherichia coli porin OmpF.
• Permeation rates through OmpF mutants were slightly reduced but still significant.
• Molecular simulations provided detailed insights into the translocation process.

Conclusions:

• Fosfomycin can efficiently cross the bacterial outer membrane via the OmpF porin.
• This study unravels the molecular basis of fosfomycin permeation.
• Findings may inform the development of other phosphonic acid-based antibiotics.