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Biophysical Investigation of Lipid Properties in Mycobacterial Lipid Membranes

Mycobacterium tuberculosis is a single infectious agent responsible for the leading cause of death worldwide i.e. Tuberculosis. The main determinant underlying the organisms’s remarkable defence mechansims are the unusal lipids constituting a robust cell envelope. Biologically most relevant mycobacterial lipid are unique form their eukaryotic counterparts in terms of structure, and thus expected to demonstrate distinct biophysical properties. We are keen in exploring mycobacterial lipid domain organization and dynamics within model membrane systems to illuminate critical lipid components as well as the role of physicochemical parameters such as temperature, pressure and growth conditions in modulating membrane organization and dynamics. We believe that such a priori mechanistic insights into the membrane properties and correlation with physicochemical factors would certainly aid in predicting the pharmacological intervention by different classes of antibacterial drugs.

The lab is particularly interested in phase transitions, fluidity and dynamics of  these biomembranes and the investigate the effect of temperature, pressure, and drugs (e.g. antibacterial and anti-TB) and other thermodynamic variables.

Lipid membranes are the most pressure sensitive biological structures, wherein the interactions are mainly stabilized by non-covalent forces such as hydrophobic and electrostatic, and pressure-dependent alteration of these weak bonds provide subtle insights into the mechanism of these stabilization forces. Pressure-dependent membrane studies often lead to the discovery of new phases and processes. Upon compression, the lipids adapt to volume restriction by changing their conformation and packing, hence high-pressure can lead to the formation of additional lipid phases, provide unprecedented information on the volume fluctuations and enthalpy changes associated with lipid transitions, not accessible with other methodologies. Finally pressure-induced novel lipid phases and pressure-modulated lateral membrane organization is now known to alter the biological activities of membrane-protein thus underscoring the importance of our aim to perform high-pressure studies for in-depth biophysical understanding of mycomembrane properties and their correlation with biological functions specially during human infections.

High-Pressure effects on (Myco) Biomembrane Assemblies

Cross talk between Eukaryotic and Mycobacterial Membrane Lipids

Many lipids from the outer cell membrane of mycobacteria can insert within the host membranes and impair their properties leading to de-regulated membrane-associated signalling during the course of infection and thus can be used by the infectious agents to their advantage. We are interested in studying their interaction with model host cell eukaryotic membranes to delineate their mechanism of toxicity to host biological membranes. Deciphering the molecular details of these interactions and possible outcomes may illuminate the mechanistic details of membrane toxicity and provide avenues for developing novel membrane-driven therapeutic approaches against tuberculosis.

Lipid Chemical Biology: Lipids as small molecule signalling motifs

The exotic cell wall components of mycobacteria are thought to be pivotal modulators of host cellular responses. Positioned at the bacterial surface, mycobacterial lipids interact with the host cell membrane thus contributing to the dynamic interplay in host-pathogen interactions. Their interaction with the host membranes modulate multiple membrane-associated host signalling pathways e.g., phosphatidylinositol metabolism thus altering membrane dynamics, or altering the GTPase signalling thus manipulating the actin cytoskeleton and vesicular trafficking. Understanding the mechanism by which specific lipids  undermines the host signalling pathways has a high potential to elucidate new therapeutic avenues to target this infectious disease.

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