Supramolecular organization and dynamics of mannosylated phosphatidylinositol lipids in the mycobacterial plasma membrane.

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a disease that claims ~1.6 million lives annually. The current treatment regime is long and expensive, and missed doses contribute to drug resistance. Therefore, development of new anti-TB drugs remains one of the highest public health priorities. Mtb has evolved a complex cell envelope that represents a formidable barrier to antibiotics. The Mtb cell envelop consists of four distinct layers enriched for Mtb specific lipids and glycans. Although the outer membrane, comprised of mycolic acid esters, has been extensively studied, less is known about the plasma membrane, which also plays a critical role in impacting antibiotic efficacy. The Mtb plasma membrane has a unique lipid composition, with mannosylated phosphatidylinositol lipids (phosphatidyl-myoinositol mannosides, PIMs) comprising more than 50% of the lipids. However, the role of PIMs in the structure and function of the membrane remains elusive. Here, we used multiscale molecular dynamics (MD) simulations to understand the structure-function relationship of the PIM lipid family and decipher how they self-organize to shape the biophysical properties of mycobacterial plasma membranes. We assess both symmetric and asymmetric assemblies of the Mtb plasma membrane and compare this with residue distributions of Mtb integral membrane protein structures. To further validate the model, we tested known anti-TB drugs and demonstrated that our models agree with experimental results. Thus, our work sheds new light on the organization of the mycobacterial plasma membrane. This paves the way for future studies on antibiotic development and understanding Mtb membrane protein function.

Influences of Vibrio cholerae Lipid A Types on LPS Bilayer Properties.

Lipopolysaccharides (LPS) present in the outer leaflet of Gram-negative bacterial outer membranes protect the bacteria from external threats and influence antibiotic permeability as well as immune system recognition. The structure of lipid A, the anchor of an LPS molecule to the outer membrane, can make direct influences on membrane properties. Particularly, in Vibrio cholerae, a Gram-negative bacterium responsible for cholera, a severe diarrheal disease, modifications of lipid A structures grant antibiotic resistance and are a primary factor that led to the current cholera pandemic. However, the difference in structural properties incurred by such modifications has not been fully explored. In this work, five symmetric bilayer systems comprised of distinct lipid A structures of Vibrio cholerae LPS with O1 O-antigen were modeled and simulated to explore influences of different lipid A types on membrane properties. All-atom molecular dynamics simulations reveal that membrane properties such as hydrophobic thickness, acyl chain order parameter, and area per lipid are largely impacted by lipid A modifications due to differences in composition and acyl chain distortions. The modified lipid A is also less negatively charged, which possibly reveals a resistance mechanism to cationic antimicrobial peptide evasion. These findings present a possible explanation for Vibrio cholerae's immune system evasion properties and establish the differences between the lipid A types, which should be of use for any future study of the Gram-negative bacteria.