RT Journal Article
SR Electronic
T1 An antibiotic-resistance conferring mutation in a neisserial porin: Structure, ion flux, and ampicillin binding
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.06.369579
DO 10.1101/2020.11.06.369579
A1 A. Bartsch
A1 C.M. Ives
A1 C. Kattner
A1 F. Pein
A1 M. Diehn
A1 M. Tanabe
A1 A. Munk
A1 U. Zachariae
A1 C. Steinem
A1 S. Llabrés
YR 2020
UL http://biorxiv.org/content/early/2020/11/06/2020.11.06.369579.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.