id8b00108_si_001.pdf (1.79 MB)
Getting Drugs into Gram-Negative Bacteria: Rational Rules for Permeation through General Porins
journal contribution
posted on 2018-07-02, 00:00 authored by Silvia Acosta-Gutiérrez, Luana Ferrara, Monisha Pathania, Muriel Masi, Jiajun Wang, Igor Bodrenko, Michael Zahn, Mathias Winterhalter, Robert A. Stavenger, Jean-Marie Pagès, James H. Naismith, Bert van den Berg, Malcolm G. P. Page, Matteo CeccarelliSmall,
hydrophilic molecules, including most important antibiotics in clinical
use, cross the Gram-negative outer membrane through the water-filled
channels provided by porins. We have determined the X-ray crystal
structures of the principal general porins from three species of Enterobacteriaceae,
namely Enterobacter aerogenes, Enterobacter
cloacae, and Klebsiella pneumoniae, and
determined their antibiotic permeabilities as well as those of the
orthologues from Escherichia coli. Starting from
the structure of the porins and molecules, we propose a physical mechanism
underlying transport and condense it in a computationally efficient
scoring function. The scoring function shows good agreement with in
vitro penetration data and will enable the screening of virtual databases
to identify molecules with optimal permeability through porins and
help to guide the optimization of antibiotics with poor permeation.