An antibiotic-resistance conferring mutation in a neisserial porin: Structure, ion flux, and ampicillin binding

Bartsch, A. and Ives, C.M. and Kattner, C. and Pein, F. and Diehn, M. and Tanabe, M. and Munk, A. and Zachariae, U. and Steinem, C. and Llabrés, S. (2021) An antibiotic-resistance conferring mutation in a neisserial porin: Structure, ion flux, and ampicillin binding. Biochimica et Biophysica Acta (BBA) - Biomembranes, 186 (6): 183601. ISSN 0005-2736

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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.

Item Type:
Journal Article
Journal or Publication Title:
Biochimica et Biophysica Acta (BBA) - Biomembranes
Uncontrolled Keywords:
Research Output Funding/yes_externally_funded
Subjects:
?? antibiotic resistancebeta-barrelsdrug-resistant infectionsx-ray crystallographyelectrophysiologymeningitisyes - externally fundednobiochemistrycell biologybiophysics ??
ID Code:
194376
Deposited By:
Deposited On:
24 May 2023 15:25
Refereed?:
Yes
Published?:
Published
Last Modified:
15 Jul 2024 23:50