Exploring functional membrane microdomains in bacterial cells to fight multi-drug resistant infections

Bacterial infections are becoming prevalent in our society due to the increasing ability of microbes to evade conventional antibiotics. Successful pathogens infections often diverge in a broad range of diseases, which enable them to escape from target-specific antibiotic therapies. Among those, the life-threatening pathogen Staphylococcus aureus is one of the most successful pathogens, causing different types of severe infections, from acute bacteremia to endocarditis, pneumonia, and chronic biofilm-associated infections. In this laboratory, we use the human pathogen Methicillin-resistant Staphylococcus aureus (MRSA) as a model organism to address a number of questions related to the cellular organization of bacteria, the compartmentalization of specific cellular processes in bacterial cells, and how these cellular processes contribute to the virulence potential of bacterial pathogens.

More specifically, this lab is interested in understanding the organization of cellular membranes in microbial cells. The organization of cellular membranes influences all cellular processes and yet, we still have a poor understanding of their organization. The pioneering fluid mosaic model (Singer and Nicolson, 1972), which proposed that membrane proteins and lipids diffuse freely and distribute homogeneously, is only an approximation of our current understanding of cell membrane organization. Cell membranes are actually a heterogeneous mixture of lipids and proteins, some of which segregate into microdomains or rafts (Simons and Ikonen, 1997). Lipid rafts are cholesterol- and sphingolipid-enriched microdomains in eukaryotic membranes, which accumulate a number of proteins associated with cellular signaling or trafficking. Lipid rafts are important for the correct functionality of numerous cellular functions, and their disruption causes serious defects in a large number of cellular processes.

We and other laboratories have contributed to the field of membrane microdomains by proving that this is a universal organization principle that affects both prokaryotic and eukaryotic membranes. Prokaryotic membranes compartmentalize in Functional Membrane Microdomains (FMM). Bacterial FMM formation requires the aggregation of isoprenoid lipids and/or cardiolipin into highly hydrophobic membrane regions and their colocalization with specific proteins. The perturbation of FMMs inevitably leads to a potent and simultaneous impairment of all harbored cellular processes, including many cellular processes related to bacterial pathogenesis, which causes a potent inhibition of the infective potential of this pathogen.

In this laboratory, we aim to understand the biological significance of bacterial FMM by performing an ambitious structural and functional characterization of these membrane platforms and the cellular processes that are allocated in these membrane structures. For this, we use cryo-electron microscopy/tomography (Cryo-EM/ET) imaging techniques to describe the structural organization of the protein machineries that are associated with FMM and we use a large number of infection and molecular techniques to dissect the role of FM in bacterial pathogenesis. In addition, we apply our knowledge in bacterial FMM to disassemble FMMs as a new strategy for anti-microbial therapy against multi-drug resistant bacterial infections.