There is an urgent need of new drugs to combat multidrug-resistant bacteria especially for Gram-negative bacteria. To date neither a robust screening method for permeability, nor well-defined physical/chemical rules governing permeation through trans-membrane channels of the outer membrane (OM) of gram-negative bacteria, are available, leading to the design of molecules with rather low permeability that require high doses usually causing toxicity issues. Recent works in literature pointed the electrostatics of the channel to be responsible for its filtering mechanism and some theoretical investigations are already reported. We combined all-atom simulations with enhanced sampling techniques to characterize the electrostatics properties of different trans-membrane channels, porins. We focused initially in the calculation of the internal electrostatics of classical porins (OmpF/OmpC and homologs) in Enterobacteriaceae, which constitute the main influx route for polar antibiotics. We extended our analysis to some specific channels from the Occ family from Pseudomonas Aeruginosa, and also the intriguing Major Outer Membrane Porin (MOMP) of Campylobacter jejeuni for which its role was not clear. The electrostatic characterization of such porins suggests that the molecular dipole moment of the diffusing molecules modulates its permeablity. The electrostatic characterization of channels together with the quantification of the size-exclusion barrier, allow us to model permeability inside gram-negative pathogens. This theoretical model allows the exploration of the chemical space to put forward the key physico-chemical properties behind permeation properties.

Modeling permeability through outer-membrane channels in gram-negative pathogens

253rd National Meeting (2017)

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