Loading...
Exploring the permeation of fluoroquinolone metalloantibiotics across outer membrane porins by combining molecular dynamics simulations and a porin-mimetic in vitro model.
Sousa, Carla F Coimbra, João T S Richter, Robert Morais-Cabral, João H Ramos, Maria J Lehr, Claus-Michael Fernandes, Pedro A Gameiro, Paula
Sousa, Carla F
Coimbra, João T S
Richter, Robert
Morais-Cabral, João H
Ramos, Maria J
Lehr, Claus-Michael
Fernandes, Pedro A
Gameiro, Paula
Citations
Altmetric:
Advisors
Editors
Other Contributors
Issue Date
2021-12-08
Submitted date
Files
Loading...
accepted manuscript
Adobe PDF, 1.52 MB
Loading...
supplementary materials
Adobe PDF, 1.33 MB
Other Titles
Abstract
The misuse and overuse of fluoroquinolones in recent years have triggered alarming levels of resistance to these antibiotics. Porin channels are crucial for the permeation of fluoroquinolones across the outer membrane of Gram-negative bacteria and modifications in porin expression are an important mechanism of bacterial resistance. One possible strategy to overcome this problem is the development of ternary copper complexes with fluoroquinolones. Compared to fluoroquinolones, these metalloantibiotics present a larger partition to the lipid bilayer and a more favorable permeation, by passive diffusion, across bacteriomimetic phospholipid-based model membranes. To rule out the porin-dependent pathway for the metalloantibiotics, we explored the permeation through OmpF (one of the most abundant porins present in the outer membrane of Gram-negative bacteria) using a multi-component approach. X-ray studies of OmpF porin crystals soaked with a ciprofloxacin ternary copper complex did not show a well-defined binding site for the compound. Molecular dynamics simulations showed that the translocation of the metalloantibiotic through this porin is less favorable than that of free fluoroquinolone, as it presented a much larger free energy barrier to cross the narrow constriction region of the pore. Lastly, permeability studies of different fluoroquinolones and their respective copper complexes using a porin-mimetic in vitro model corroborated the lower rate of permeation for the metalloantibiotics relative to the free antibiotics. Our results support a porin-independent mechanism for the influx of the metalloantibiotics into the bacterial cell. This finding brings additional support to the potential application of these metalloantibiotics in the fight against resistant infections and as an alternative to fluoroquinolones.
Citation
Biochim Biophys Acta Biomembr. 2021 Dec 8:183838. doi: 10.1016/j.bbamem.2021.183838. Epub ahead of print.
Publisher
PubMed ID
PubMed Central ID
Additional Links
Embedded video
Type
Article
Language
en
Description
Series/Report no.
ISSN
EISSN
1879-2642
ISBN
ISMN
Gov't Doc #
Sponsors
License
Attribution-NonCommercial-NoDerivatives 4.0 International