Translocation of Phosphonic Acid Antibiotics Through Bacterial Outer Membrane Channels

  • The outer membrane of Gram-negative bacteria acts as a formidable barrier for the passage of substances from the external environment to the inside of the bacterium. Understanding the permeation of antibiotics through bacterial outer membrane channels is a subject of great interest to overcome the resistance and permeability problems associated with the translocation of antibiotics. The present Ph.D. thesis aims to understand the permeation of phosphonic acid-containing antibiotics through bacterial outer membrane channels. In the first part, the permeation of fosfomycin through the porin OmpF of Escherichia coli has been investigated using molecular dynamics and Brownian dynamics simulations and is complementary to the electrophysiology experiments. This study aims to understand the permeation of fosfomycin and estimate the free energy barriers involved in the respective permeation process. Two OmpF triple mutants have been investigated to illustrate the effect of OmpF mutations on the translocation properties of fosfomycin. A high rate of fosfomycin diffusion through wild-type OmpF has been observed along with low permeation energy barriers, while higher barriers have been obtained for the studied mutants. In the second part, the translocation mechanism of various anionic solutes, i.e., from simple ions to complex antibiotics through the OprO channel of Pseudomonas aeruginosa has been explored using metadynamics and umbrella sampling methods. Aspects of the free energy convergence and the role of the complexity of the permeating solutes in determining free energy surfaces have been demonstrated. Further, the permeation of fosfomycin and fosmidomycin through the phosphate specific OprP and OprO channels of Pseudomonas aeruginosa has been discussed. The findings presented in this thesis provide the atomistic and functional aspects of permeation processes through the outer membrane channels of Gram-negative bacteria.

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Publishing Institution:IRC-Library, Information Resource Center der Jacobs University Bremen
Granting Institution:Jacobs Univ.
Referee:Ulrich Kleinekathöfer, Mathias Winterhalter, Roland Benz, Lars Schäfer
Advisor:Ulrich Kleinekathöfer
Persistent Identifier (URN):urn:nbn:de:gbv:579-opus-1009470
Document Type:PhD Thesis
Date of Successful Oral Defense:2020/09/14
Date of First Publication:2021/01/19
Academic Department:Physics & Earth Sciences
PhD Degree:Biochemical Engineering
Focus Area:Health
Call No:2020/16

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