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Discovery and characterization of new bacterial cell wall targets and inhibitors to treat resistant infections

治疗耐药感染的新细菌细胞壁靶点和抑制剂的发现和表征

基本信息

批准号：
10541882
负责人：
Daniel Kahne
金额：
$ 76.72万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541882
关键词：
Acceleration Anabolism Anti-Bacterial Agents Antibiotic Resistance Antibiotics Bacteria Bacterial Antibiotic Resistance Bacterial Infections Binding Biochemical Biochemistry Biological Biological Assay Cell Separation Cell Wall Cell division Cell membrane Cell surface Cells Cellular biology Chemicals Collaborations Collection Complex Cytoplasm Development Enzymatic Biochemistry Enzymes Family Foundations Glean Glucosaminidase Glycopeptides Goals Grant Health Human Hydrolase In Vitro Infection Knowledge Learning Letters Lipids Membrane Potentials Membrane Proteins Methods Molecular Conformation Nature Organism Pathogenesis Pathway interactions Peptidoglycan Peptidyltransferase Physiology Play Polymerase Polymers Process Proteins Publishing Recording of previous events Research Research Support Resistance Role Staphylococcus aureus Staphylococcus aureus infection Structure Vancomycin Variant amidase analog bacterial genetics bacterial resistance beta-Lactams crosslink daughter cell design enzyme structure genetic approach high throughput screening inhibitor insight muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol mutant novel novel strategies programs protein complex reconstitution response technological innovation tool

项目摘要

Project Summary Antibiotic-resistant bacterial infections pose a substantial and growing threat to human health. There is a pressing need to characterize new antibacterial targets and to develop methods that enable discovery and characterization of inhibitors for these targets. The research described here focuses on understanding late steps in the assembly of the peptidoglycan cell wall that surrounds bacterial cells. The cell wall is essential for bacterial survival, making it an outstanding target for antibiotics. Indeed, some of the most important antibiotics in history, the beta-lactams and the glycopeptides, target late steps in peptidoglycan assembly. Historically, the enzymes that catalyze these late steps have been extremely difficult to study due to the nature of the substrates that are required, the products that are formed, and the fact that many peptidoglycan biosynthetic enzymes are polytopic membrane proteins or function only when complexed to a membrane protein. Recent technological innovations made in our labs have advanced the field of peptidoglycan biosynthesis considerably, and we are able to pursue challenging targets that have not previously been studied. This project has four aims. Aim 1 involves further development of chemical tools to enable mechanistic and structural studies of cell wall biosynthetic enzymes. Aim 2 focuses on understanding MurJ, the flippase that exports the peptidoglycan precursor Lipid II from the cytoplasm to the cell surface where it is polymerized to produce peptidoglycan. Aim 3 focuses on characterizing FtsW, the only universally conserved peptidoglycan polymerase in bacteria. Aim 4 focuses on two novel Staphylococcus aureus cell wall hydrolase complexes that process uncrosslinked peptidoglycan before it is integrated into the cell wall. These four aims will provide fundamental information on how the bacterial cell wall is built. The studies will also provide new chemical tools, assays, and scientific knowledge to enable the discovery of inhibitors that may be useful for treating resistant bacterial infections.

项目总结