Free Energy Barriers for Passive Drug Transport through the Mycobacterium tuberculosis Outer Membrane: A Molecular Dynamics Study

Abstract

The emergence of multi-drug-resistant tuberculosis strains poses a significant challenge to modern medicine. The development of new antituberculosis drugs is hindered by the low permeability of many active compounds through the extremely strong bacterial cell wall of mycobacteria. In order to estimate the ability of potential antimycobacterial agents to diffuse through the outer mycolate membrane, the free energy profiles, the corresponding activation barriers, and possible permeability modes of passive transport for a series of known antibiotics, modern antituberculosis drugs, and prospective active drug-like molecules were determined using molecular dynamics simulations with the all-atom force field and potential of mean-force calculations. The membranes of different chemical and conformational compositions, density, thickness, and ionization states were examined. The typical activation barriers for the low-mass molecules penetrating through the most realistic membrane model were 6–13 kcal/mol for isoniazid, pyrazinamide, and etambutol, and 19 and 25 kcal/mol for bedaquilin and rifampicin. The barriers for the ionized molecules are usually in the range of 37–63 kcal/mol. The linear regression models were derived from the obtained data, allowing one to estimate the permeability barriers from simple physicochemical parameters of the diffusing molecules, notably lipophilicity and molecular polarizability.

Temperature-Induced Restructuring of Mycolic Acid Bilayers Modeling the Mycobacterium tuberculosis Outer Membrane: A Molecular Dynamics Study

“…In keeping with the approach employed in our previous works [44,49] to study the structures of mycolate-based outer Mtb membranes and their free energy profiles regarding the transverse diffusion of drug molecules, specially constructed model membranes based on symmetrical mycolic acid bilayers with different component compositions and thicknesses were considered in the analysis. We believe that the choice of symmetrical systems consisting of free MA molecules is justified because they represent rather simple prototypical models that allow one to significantly reduce the number of variable parameters and thus the uncertainty and complexity of modeling.…”

“…Thus, the model is likely to somewhat overestimate the inner leaflet fluidity and underestimate the outer leaflet fluidity compared to the natural membranes. However, the mycolate bilayer serves as a strong "framework" that determines the OM's protective properties, and the MA packing and voids in it largely control the diffusion [49]. The inner leaflet's barrier role is believed to dominate, and the overall model bias in the analysis of diffusion and temperature effects should not be critical.…”