Protein Structure and Function
Instituto de Química Física "Rocasolano" CSIC (IQFR)
DESCRIPTION OF THE OFFER
Structure, Dynamics and Regulation of the Bacterial Wall. Implications in Antibiotic Resistance
The bacterial peptidoglycan (PG) is an essential gigantic macromolecule that defines the shape of the bacterium and enables the bacterium to resist lysis as a result of its high intracellular osmotic pressure. Because the cell wall is structurally specific of bacteria, the steps involved in regulation of cell-wall biosynthesis are the targets of numerous antibiotics, including the beta-lactams that represent >50% of the available contemporary antibiotic arsenal. This project intends multidimensional dissection (structural, biochemical, biophysical and pre-clinical) of some essential bacterial processes pivoting around the bacterial cell wall. Specifically, this project addresses the study of four main topics:
- Regulation of PG hydrolases in bacterial cell division.
- Host-Pathogen interactions mediated by cell wall anchored proteins.
- Cell wall remodeling and outer membrane stabilization by LD-transpeptidases.
- PG recycling and antibiotics resistance mechanisms in MDR pathogens.
Our project intends to provide insights about orchestration between cell wall synthesis and remodeling to maintain the integrity of cell wall during four fundamental processes some of them with very important implications in antibiotics resistance. State-of-the-art experimental approaches will be used including the use of protein engineering, lipid cubic phases, X-ray diffraction, cryo EM, nanodiscs, biophysical characterization, bioinformatics, and finally, in vitro cell culture infection studies. These processes are of the outmost relevance in both fundamental and applied sides. Unveiling the molecular basis of these mechanisms paves the way to identify new drug targets and to develop antimicrobial drugs effective against multidrug-resistant clinical strains and withnew modes of action that will make the development of resistance less likely.
This project is performed in collaboration with different world top leaders.
Juan A. Hermoso Domínguez