Getting Drugs into Gram-Negative Bacteria: Rational Rules for Permeation through General Porins Acosta-GutiérrezSilvia FerraraLuana PathaniaMonisha MasiMuriel WangJiajun BodrenkoIgor ZahnMichael WinterhalterMathias StavengerRobert A. PagèsJean-Marie NaismithJames H. van den BergBert G. P. PageMalcolm CeccarelliMatteo 2018 Small, 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 <i>Enterobacter aerogenes</i>, <i>Enterobacter cloacae</i>, and <i>Klebsiella pneumoniae</i>, and determined their antibiotic permeabilities as well as those of the orthologues from <i>Escherichia coli</i>. 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.