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Permeation of β-Lactamase Inhibitors through the General Porins of Gram-Negative Bacteria

Pira, A; Scorciapino, MA; Bodrenko, IV; Bosin, A; Acosta-Gutiérrez, S; Ceccarelli, M; (2020) Permeation of β-Lactamase Inhibitors through the General Porins of Gram-Negative Bacteria. Molecules , 25 (23) , Article 5747. 10.3390/molecules25235747. Green open access

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Abstract

Modern medicine relies upon antibiotics, but we have arrived to the point where our inability to come up with new effective molecules against resistant pathogens, together with the declining private investment, is resulting in the number of untreatable infections increasing worldwide at worrying pace. Among other pathogens, widely recognized institutions have indicated Gram-negative bacteria as particularly challenging, due to the presence of the outer membrane. The very first step in the action of every antibiotic or adjuvant is the permeation through this membrane, with small hydrophilic drugs usually crossing through protein channels. Thus, a detailed understanding of their properties at a molecular level is crucial. By making use of Molecular Dynamics simulations, we compared the two main porins of four members of the Enterobacteriaceae family, and, in this paper, we show their shared geometrical and electrostatic characteristics. Then, we used metadynamics simulations to reconstruct the free energy for permeation of selected diazobicyclooctans through OmpF. We demonstrate how porins features are coupled to those of the translocating species, modulating their passive permeation. In particular, we show that the minimal projection area of a molecule is a better descriptor than its molecular mass or the volume. Together with the magnitude and orientation of the electric dipole moment, these are the crucial parameters to gain an efficient compensation between the entropic and enthalpic contributions to the free energy barrier required for permeation. Our results confirm the possibility to predict the permeability of molecules through porins by using a few molecular parameters and bolster the general model according to which the free energy increase is mostly due to the decrease of conformational entropy, and this can be compensated by a favorable alignment of the electric dipole with respect to the channel intrinsic electric field.

Type: Article
Title: Permeation of β-Lactamase Inhibitors through the General Porins of Gram-Negative Bacteria
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.3390/molecules25235747
Publisher version: https://doi.org/10.3390/molecules25235747
Language: English
Additional information: This is an open access article distributed under the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: beta-lactamase inhibitors; molecular dynamics simulations; Gram-negative bacteria; bacterial porins; free energy surface; permeation of small molecules
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/10117691
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