Final published version
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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - An antibiotic-resistance conferring mutation in a neisserial porin: Structure, ion flux, and ampicillin binding
AU - Bartsch, A.
AU - Ives, C.M.
AU - Kattner, C.
AU - Pein, F.
AU - Diehn, M.
AU - Tanabe, M.
AU - Munk, A.
AU - Zachariae, U.
AU - Steinem, C.
AU - Llabrés, S.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - 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.
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.
KW - Antibiotic resistance
KW - Beta-barrels
KW - Drug-resistant infections
KW - X-ray crystallography
KW - Electrophysiology
KW - Meningitis
U2 - 10.1016/j.bbamem.2021.183601
DO - 10.1016/j.bbamem.2021.183601
M3 - Journal article
VL - 186
JO - Biochimica et Biophysica Acta (BBA) - Biomembranes
JF - Biochimica et Biophysica Acta (BBA) - Biomembranes
SN - 0005-2736
IS - 6
M1 - 183601
ER -