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Investigation of mechanism and inhibition of lipid transporters involved in bacterial cell wall biogenesis
Third-party funded project
Project title Investigation of mechanism and inhibition of lipid transporters involved in bacterial cell wall biogenesis
Principal Investigator(s) Perez, Camilo
Organisation / Research unit Departement Biozentrum / Structural Biology (Perez)
Department Departement Biozentrum / Structural Biology (Perez)
Project start 01.07.2021
Probable end 30.06.2023
Status Completed
Abstract

Bacterial infections represent a major public health problem of broad concern to countries and multiple sectors, augmented by 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 communityacquired infections affecting several parts of the human body. 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 distinct features of Gram-positives cell wall is the presence of teichoic acids (TA). These biopolymers are found embedded or covalently linked to the peptidoglycan (PG) layer, and have been shown to be important for immune evasion, ion homeostasis, adhesion, biofilm formation, and for protection against antimicrobials. Despite their great importance, structural, mechanistic and fundamental biochemical aspects of membrane proteins participating in TA assembly are scarce. TA biosynthesis generally require transport of lipids across the plasma membrane of bacteria, involving the participation of active and passive lipid transporters. The transported lipids can be either carriers of TA precursors, anchors of TA polymers, or finished TA molecules. Transporters that mediate the translocation of these lipids are fundamental players in TA biosynthesis routes, and in consequence are valuable drugs targets. My lab is interested in understanding the mechanism of lipid transporters involved in TA synthesis, evaluate their role in cell function, and in investigating modes of activity inhibition. Our results will provide the frame for structure-based design of novel inhibitors targeting TA synthesis. In combination, our results will provide a mechanistic understanding of multiple transport processes highly relevant for TA biosynthesis, and describe potential modes of activity modulation and inhibition.

Financed by Swiss National Science Foundation (SNSF)
   

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