ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
1/3
Fluoroqunolone ms.pdf (1.82 MB)

Dynamic Interaction of Norfloxacin to Magnesium Monitored by Bacterial Outer Membrane Nanopores

preprint
submitted on 18.05.2020 and posted on 19.05.2020 by Jiajun Wang, Jigneshkumar Dahyabhai Prajapati, Ulrich Kleinekathöfer, Mathias Winterhalter
The effect of divalent ions on the permeability of norfloxacin across the major outer membrane channels from E. coli (OmpF, OmpC) and E. aerogenes (Omp35, Omp36) has been investigated at the single channel level. To understand the rate limiting steps in permeation, we reconstituted single porin into planar lipid bilayers and analyzed the ion current fluctuations caused in the presence of norfloxacin. To obtain an atomistic view, we complemented the experiments with millisecond-long free energy calculations based on temperature-accelerated Brownian dynamics simulations to identify the most probable permeation pathways of the antibiotics through the respective pore. Both, experimental analysis and computational modelling, suggest that norfloxacin is able to permeate through the larger porins, i.e., OmpF, OmpC, and Omp35, whereas it only binds to the slightly narrower porin Omp36. Moreover, divalent ions can bind to negatively charged residues inside the porin, reversing the ion selectivity of the pore. In addition, the divalent ions can chelate with the fluoroquinolones and alter their physicochemical properties. The results suggest that the conjugation must break with either one of them when the antibiotics molecules bypass the lumen of the porin, with the conjugation to the antibiotic being more stable than that to the pore. In general, the permeation or binding process of fluoroquinolone in porins occurs irrespective of the presence of divalent ions, but the presences of divalent ions can vary the kinetics significantly.

Funding

National Natural Science Foundation of China (61901171)

Deutsche Forschungsgemeinschaft (DFG) through project KL1299/9-2

European Union seventh framework programme (FP7/2007-2013) and EFPIA companies.

EU FP7-PEOPLE-2013-ITN, Marie-Skłodowska Curie Translocation network Nr. 607694.

History

Email Address of Submitting Author

jiajun.wang@outlook.de

Institution

Nanjing University

Country

China

ORCID For Submitting Author

0000-0003-3420-6376

Declaration of Conflict of Interest

No conflict of interests

Exports

Logo branding

Exports