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Abstract
Gram-negative bacteria cause the majority of highly drug-resistant bacterial infections. To cross the outer membrane of the complex Gram-negative cell envelope, antibiotics permeate through porins, trimeric channel proteins that enable the exchange of small polar molecules. Mutations in porins contribute to the development of drug-resistant phenotypes. In this work, we show that a single point mutation in the porin PorB from Neisseria meningitidis, the causative agent of bacterial meningitis, can strongly affect the binding and permeation of beta-lactam antibiotics. Using X-ray crystallography, high-resolution electrophysiology, atomistic biomolecular simulation, and liposome swelling experiments, we demonstrate differences in drug binding affinity, ion selectivity and drug permeability of PorB. Our work further reveals distinct interactions between the transversal electric field in the porin eyelet and the zwitterionic drugs, which manifest themselves under applied electric fields in electrophysiology and are altered by the mutation. These observations may apply more broadly to drug-porin interactions in other channels. Our results improve the molecular understanding of porin-based drug-resistance in Gram-negative bacteria.
Original language | English |
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Article number | 183601 |
Number of pages | 11 |
Journal | BBA - Biomembranes |
Volume | 1863 |
Issue number | 6 |
Early online date | 3 Mar 2021 |
DOIs | |
Publication status | Published - 1 Jun 2021 |
Keywords
- Antibiotic resistance
- Beta-barrels
- Drug-resistant infections
- Electrophysiology
- Meningitis
- X-ray crystallography
ASJC Scopus subject areas
- Biophysics
- Biochemistry
- Cell Biology
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Dive into the research topics of 'An antibiotic-resistance conferring mutation in a neisserial porin: Structure, ion flux, and ampicillin binding'. Together they form a unique fingerprint.Projects
- 1 Finished
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Stabilising G-Protein Coupled Receptors in Solution With Cholesterol-Based Detergents for Drug Discovery Purposes
Fraser, N. (Investigator) & Hopkins, A. (Investigator)
1/07/13 → 31/12/14
Project: Research