CANCELED - Mechanism of cell wall transporters involved in teichoic acid synthesis

Bacterial infections represent a major public health problem of broad concern, augmented by the increasing occurrence of strains resistant to antibacterial agents. Pathogens such as the Gram-positive bacteria Staphylococcus aureus and Streptococcus pneumoniae are leading causes of nosocomial and community-acquired infections. The bacterial cell wall is a complex structure that exerts important protective functions against host defenses and antibiotics allowing bacterial survival and adaptation under adverse conditions. One of the most distinctive features of the Gram-positive cell wall are teichoic acid (TA) biopolymers. TA, covalently linked to the peptidoglycan layer or anchored to the plasma membrane, have been shown to be fundamental for immune evasion, adhesion, biofilm formation, and protection against antimicrobials. Membrane transporters that mediate the translocation of lipidic and water-soluble precursors are fundamental players in TA synthesis pathways, and in consequence, are valuable drugs targets. My lab is interested in understanding the mechanism of these proteins, evaluate their role in cell function, and develop strategies for the inhibition of their activity. To answer our scientific questions, my Lab uses single-particle cryo-EM, X-ray crystallography, screening of substrates and inhibitors by Solid-Supported-Membranes (SSM) electrophysiology, selection of nanobodies, multiple biochemical and biophysical techniques, and in vitro bacterial assays. In the last years, my Lab has investigated the activity, specificity, and inhibition of transporters participating in TA synthesis in S. aureus and S. pneumoniae. We have elucidated structures of fundamental conformational states of these proteins and described previously unknown architectural features essential to understanding their mechanisms. We have also shown how their activity contributes to adaptation under stress conditions and have established a framework for generating drug inhibitors targeting these proteins.