Open AccessRole of internal loop dynamics in antibiotic permeability of outer membrane porins
Author(s) -
Archit Vasan,
Nandan Haloi,
Rebecca Joy Ulrich,
Mary Elizabeth Metcalf,
PoChao Wen,
William W. Metcalf,
Paul J. Hergenrother,
Diwakar Shukla,
Emad Tajkhorshid
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2117009119
Subject(s) - porin , bacterial outer membrane , mutant , bacteria , biophysics , chemistry , antibiotics , permeation , membrane , escherichia coli , biology , biochemistry , genetics , gene
Significance Antibiotic resistance in Gram-negative pathogens has been identified as an urgent threat to human health by the World Health Organization. The major challenge with treating infections by these pathogens is developing antibiotics that can traverse the dense bacterial outer membrane (OM) formed by a mesh of lipopolysaccharides. Effective antibiotics permeate through OM porins, which have evolved for nutrient diffusion; however, the conformational states of these porins regulating permeation are still unclear. Here, we used molecular dynamics simulations, free energy calculations, Markov-state modeling, and whole-cell accumulation assays to provide mechanistic insight on how a porin shifts between open and closed states. We provide a mechanism of how Gram-negative bacteria confer resistance to antibiotics.