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

A fundamental feature of mycobacterial cell envelope that underlines its robust response to drugs and host responses is the unique lipid repertoire spatially distributed across the inner and outer membranes. However, the correlation of spatially distinct lipid composition and properties in mycobacterial membranes with pathogenicity and drug interactions is extremely poorly understood. In this work, we report distinct hydration states of the mycobacterial inner and outer layers with lipid-structure dictated solvation relaxation kinetics, rotational mobility and lateral lipid diffusion. First ever reported simulation on mycobacterial membranes shows this solvation dynamics to be governed by specific lipid clustering patterns in the two layers of cell envelope modulating water abundance and interactions with lipid head groups. As lipid structure-dependent membrane properties are likely to play a central role in the development of bacterial survival and resistance to drugs. Thus, understanding how mycobacterial inner and outer membrane lipid composition changes membrane properties in a spatially resolved fashion is likely to lead to new anti-infective strategies and deepen our understanding of these spatially and compositionally distinct membrane platforms and their plausible functional roles in bacterial survival, drug resistance, and pathogenesis.