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Exploiting the porin pathway for polar compound delivery into Gram-negative bacteria

Scorciapino, MA; D'Agostino, T; Acosta-Gutierrez, S; Malloci, G; Bodrenko, I; Ceccarelli, M; (2016) Exploiting the porin pathway for polar compound delivery into Gram-negative bacteria. Future Medicinal Chemistry , 8 (10) pp. 1047-1062. 10.4155/fmc-2016-0038. Green open access

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Abstract

BACKGROUND. In Gram-negative bacteria, the outer-membrane represents an additional barrier antibiotics have to overcome to permeate inside pathogens. Our inability to come up with novel effective antibiotics mostly relies upon insufficient understanding of the molecular basis behind outer-membrane penetration. RESULTS. Polar antibiotics can permeate through water-filled porins. Through molecular modeling, permeation of imipenem and meropenem through porins was found to strongly depend upon capability of drugs to properly align their electric dipole to the internal electric field in the restricted region of the pore. Electrostatics differences between OmpF and OmpC, and modifications along a series of OmpC mutants from E. coli resistant clinical strains identify a “pre-orientation” region, which dramatically affects antibiotic path. Electrostatics modifications along a series of porin mutants from resistant clinical strains identify a “pre-orientation” region, which dramatically affects antibiotic pathway. CONCLUSIONS. A novel perspective is presented, suggesting new molecular properties to be included in drug design.

Type: Article
Title: Exploiting the porin pathway for polar compound delivery into Gram-negative bacteria
Open access status: An open access version is available from UCL Discovery
DOI: 10.4155/fmc-2016-0038
Publisher version: http://doi.org/10.4155/fmc-2016-0038
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Antimicrobial drugs, drug design, computational chemistry and molecular modelling
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10062602
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