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Getting drugs into Gram-negative bacteria: Rational rules for permeation through general porins

DOI: 10.1021/acsinfecdis.8b00108 DOI Help

Authors: Silvia Acosta-gutierrez (University of Cagliari) , Luana Ferrara (University of St Andrews) , Monisha Pathania (Institute for Cell and Molecular Biosciences, Newcastle University) , Muriel Masi (Aix-Marseille Université) , Jiajun Wang (Jacobs University Bremen) , Igor Bodrenko (University of Cagliari) , Michael Zahn (Institute for Cell and Molecular Biosciences, Newcastle University) , Mathias Winterhalter (Jacobs University Bremen) , Robert A. Stavenger (GlaxoSmithKline) , Jean-marie Pages (Aix-Marseille Université) , James H. Naismith (University of Oxford) , Bert Van Den Berg (Institute for Cell and Molecular Biosciences, Newcastle University) , Malcolm G. P. Page (Jacobs University Bremen) , Matteo Ceccarelli (University of Cagliari)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Infectious Diseases

State: Published (Approved)
Published: July 2018

Abstract: 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 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.

Journal Keywords: bacteria; antibiotics; rational design; porins structure; transport; scoring function

Subject Areas: Biology and Bio-materials, Medicine