Lipid Clustering in Mycobacterial Cell Envelope Layers Governs Spatially Resolved Solvation Dynamics

Abstract

The mycobacterial cell envelope acts as a multilayered barrier to drugs. However, the role of lipid composition in the properties of different mycobacterial membranes, otherwise dictating their interactions with drugs, is poorly understood. In this study, we found that hydration states, solvation relaxation kinetics, rotational lipid mobility, and lateral lipid diffusion differed between inner and outer mycobacterial membranes. Molecular modeling showed that lipid clustering patterns governed membrane dynamics in the different layers of the cell envelope. By regulating membrane properties, lipid composition and structure modulated water abundance and interactions with lipid head groups. These findings can help deepen our understanding of the physical chemistry underlying membrane structure and function, as well as the interaction of mycobacterial membranes with drugs and host membranes.

Effect of Host Cholesterol on the Membrane Dynamics of Outer Membrane Lipids of Mycobacteria

“…We also generated independent insights on the preferential location sites of exogenous Chol using previously defined molecular models of Msm OML (refs). [34] Chol either clustered together and localized within the disordered region (the thinner region of the membranes) in line with AFM and FLIM results, but also at the interface of L o -L d ; ordered and disordered region. This could reduce the line tension at the phase boundary and stabilize the phase-segregated OML bilayer (Figure 5A).…”

Molecular Modeling and Simulation of the Mycobacterial Cell Envelope: From Individual Components to Cell Envelope Assemblies

“…Adhyapak et al recently proposed and simulated a first simplified all-atom model containing Ac 2 PIM 2 , CL, PE, PI, diacylglycerol, and phosphatidylglycerol (PG). 54 Li et al 41 proposed a symmetric all-atom model containing PI, PE, and CL as well as PIM 2 and PIM 6 , while Brown et al constructed both asymmetric and symmetric MIM models using coarse-grained MD simulations (Figure 3). 5 The ■ REALISTIC MYCOBACTERIAL CELL ENVELOPES:…”

“…19,26,53 In the future, the ultimate goal would be to design MOM models constituted of the ensemble of lipids presented above to see how they can assemble and organize. A very first attempt to model the MOM was recently presented, 54 but it requires further developments to really understand the biophysical properties of such membranes at the molecular level. To illustrate our view, here, we propose an outer leaflet model of MOM (Figure 2).…”

Fusion Landscape of Mycobacterial Envelope-Derived Lipid Vesicles with Intact Bacteria Dictates High Intracellular Drug Retention

“…Tuberculosis (TB), an infectious disease, caused by Mycobacterium tuberculosis (Mtb) accounts for the highest morbidity and mortality every year. 1 The current treatment course of antitubercular therapy (anti-TB) with a high frequency of oral drug administration for a longer duration leads to the patient's noncompliance and a high risk of developing acquired drug resistance. 2 Hence, there is a scope to devise newer strategies that could help in lessening the pill burden, duration of medication, and adverse effects with improved treatment to overcome the disease.…”

“…Tuberculosis (TB), an infectious disease, caused by Mycobacterium tuberculosis ( Mtb ) accounts for the highest morbidity and mortality every year . The current treatment course of antitubercular therapy (anti-TB) with a high frequency of oral drug administration for a longer duration leads to the patient’s noncompliance and a high risk of developing acquired drug resistance .…”