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Co-opting Endogenous Pathogen Autolysins as Next Generation Antibiotics

选择内源性病原体自溶素作为下一代抗生素

基本信息

批准号：
10053699
负责人：
Karl E Griswold
金额：
$ 54.77万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-11-18 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053699
关键词：
Acinetobacter Address Anti-Bacterial Agents Antibiotic Resistance Antibiotics Autolysin Bacteria Bacterial Drug Resistance Bacterial Infections Bacterial Physiology Bacteriophages Bioinformatics Biological Assay Biological Response Modifier Therapy British Cell Wall Centers for Disease Control and Prevention (U.S.)Cessation of life Clinical Cytolysis Development Directed Molecular Evolution Drug resistance ESKAPE pathogens Engineering Enterobacteriaceae Enterococcus faecium Enzymes Exhibits Fluorescence-Activated Cell Sorting Future Gel Genetic Engineering Genome Genomic Library Genus staphylococcus Goals Government Harvest Health Human Hydrolase Immune system In Vitro Klebsiella pneumoniae Lead Libraries Life LytA enzyme Lytic Maintenance Metagenomics Methods Molecular Muramidase Nature Organism Pathogenicity Pathway interactions Peptidoglycan Performance Pharmaceutical Preparations Phenotype Predisposition Process Proteome Pseudomonas aeruginosa Recombinants Refractory Reporting Resistance Resistance development Specificity Staphylococcus aureus Testing Therapeutic Trust Ursidae Family Work antimicrobial drug bacterial resistance bacteriocin burden of illness cellular targeting chemotherapy clinically relevant combinatorial cost drug resistant bacteria endolysin enzyme activity enzyme therapy experience experimental study high throughput screening improved in vivo innovation lead candidate lead optimization methicillin resistant Staphylococcus aureus microbial next generation novel novel therapeutics pathogen pathogenic bacteria resistant strain screening side effect small molecule

项目摘要

Summary: Antibiotic resistance represents one of the greatest threats to human health. In particular, the six so-called ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and enterobacteriaceae) represent highly drug-resistant bacteria that exert a tremendous global burden of disease. The potential scope of this crisis was highlighted in a recent report commissioned by the Wellcome Trust and British Government; the authors projected that, by 2050, drug-resistant bacterial infections could cost the global economy a cumulative $100 trillion and kill 10 million people annually. To address this issue, there is a critical need for innovative antibacterial treatments. One compelling therapeutic strategy leverages recombinant enzymes that degrade cell wall peptidoglycan, thereby causing bacterial lysis and death. Currently, all such lytic enzyme therapies are trans-acting in nature, i.e., they are derived from bacteriophage or the immune systems of eukaryotic organisms. This proposal seeks to establish an entirely new paradigm for developing bacteriolytic enzyme drugs. We hypothesize that a pathogen's own endogenous cell wall hydrolases (i.e., “autolysins”) can be co-opted to yield potent antimicrobial agents that are refractory to new resistance phenotypes. To test this hypothesis, we will pursue initial studies with the high impact pathogen methicillin resistant S. aureus (MRSA), although the strategy should be broadly applicable to any bacterial pathogen. Here, complementary computational and experimental approaches will be utilized to identify, isolate, and engineer potent autolysins derived from staphylococcal proteomes. In aim 1, the sequenced genome of S. aureus and related bacteria will be searched for autolysins using bioinformatics. Candidate enzymes will be cloned, evaluated, and their activities will be improved via computationally guided fusion to high performance cell wall targeting domains. In aim 2, a complementary high throughput screening strategy will be taken to identify autolysins from genomic libraries of pathogenic staphylococci. The activities of candidate enzymes will be improved via combinatorial chimeragenesis with high performance cell wall targeting domains, followed by high throughput functional screening of the resultant chimeric libraries. In aim 3, lead autolysin candidates will be further engineered for potent anti-staphylococcal activity using a directed evolution strategy. The most promising lead candidates from these studies will be rigorously evaluated using a panel of clinically relevant in vitro and in vivo assays. Ultimately, this project could yield both novel anti-staphylococcal agents and an entirely new paradigm for development of antibacterial biotherapies.

简介:

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bioinformatics-driven discovery of novel Clostridioides difficile lysins and experimental comparison with highly active benchmarks.

DOI：
10.1002/bit.27759
发表时间：
2021-07
期刊：
BIOTECHNOLOGY AND BIOENGINEERING
影响因子：
3.8
作者：
Furlon, Jacob M.;Mitchell, Spencer J.;Bailey-Kellogg, Chris;Griswold, Karl E.
通讯作者：
Griswold, Karl E.

Nonclassical antagonism between human lysozyme and AMPs against Pseudomonas aeruginosa.