Water-Based Screening of Antibiotics Permeability

Abstract

Multi-drug resistance bacteria are a challenging problem of contemporary medicine. A new molecular framework for identifying and developing new antinfectives is needed. This is especially true for Gram-negative bacteria where the presence of the additional outer membrane (OM) hinders the access to internal targets.1 In the OM, general diffusion porins are expressed to facilitate the entry of polar molecules, and today porins are believed to be the main pathway for polar antibiotics. Bacteria can develop resistance by reducing the OM permeability, either by modulating the expression of porins, or by selecting key residues mutations that alter the permeability of the porins themselves.2 The discovery of new effective polar antibiotics passes through the determination of the electrostatic interactions controlling translocation through porins.3Aiming to reveal the electrostatic field inside bacterial porins, we have developed a Molecular Dynamics based method to explore the electrostatics of any solvated protein.4 This method allows us not only to shed some light on protein electrostatics but also to investigate the effects caused by media conditions, e.g., pH and ion concentration, with full atom resolution. Furthermore, using the electrostatic profile of the channel and simple physico-chemical properties of antibiotics, we have implemented a simple theoretical model to score drugs for their permeability. These results may have important implications for the formulation of a general model for antibiotics translocation, and can be taken into account for screening molecules with improved permeation properties in rational drug designing.1. Nikaido, H. Microbiol Mol Biol Rev 67, 593-656 (2003).2. Lou, H. et al. PLoS ONE 6, e25825 (2011).3. A. Kumar et al. J Phys Chem B 114, 9608-9616 (2010).4. S. Acosta-Gutierrez. J Phys Chem Lett 6, 1807-1812 (2015).