Antibiotic-sparing strategies targeting outer membrane ushers in Gram-negative bacterial pathogens

针对外膜的抗生素节约策略迎来革兰氏阴性细菌病原体

• 批准号: 10352470
• 负责人: Peng Yuan
• 金额: $ 36.09万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352470
• 关键词: Acinetobacter; Address; Adhesions; Age; Antibiotic Resistance; Antibiotics; Antibodies; Bacterial Adhesins; Bacterial Drug Resistance; Bacterial Infections; Bacteriology; Binding; Biochemical; Biogenesis; Biological Assay; Biology; Bordetella pertussis; Campylobacter; Cell Membrane Permeability; Centers for Disease Control and Prevention (U.S.); Chemicals; Communities; Complex; Development; Diagnosis; Drug resistance; Drug-resistant Campylobacter; Enterobacteriaceae; Escherichia coli; Extended-spectrum β-lactamase; Fiber; Fimbriae Proteins; Funding Opportunities; Gram-Negative Bacteria; Habitats; Immunoglobulins; Immunology; In Vitro; Individual; Infection; International; Knowledge; Ligand Binding Domain; Mediating; Membrane; Microbial Biofilms; Molecular; Molecular Chaperones; Molecular Conformation; Monoclonal Antibodies; Multi-Drug Resistance; Nature; Pathway interactions; Permeability; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pilum; Predisposition; Prevention therapy; Pseudomonas aeruginosa; Public Health; Reporting; Role; Salmonella; Shapes; Shigella; Structure; Surface; System; Tertiary Protein Structure; Therapeutic; Therapeutic Monoclonal Antibodies; Tissues; United States; Urinary tract infection; Uropathogenic E. coli; Usher Proteins; Virulence; Virulence Factors; Work; alternative treatment; antibiotic resistant infections; appendage; base; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; combat; drug resistant pathogen; efficacy testing; experience; extracellular; in vivo; inhibitor; innovation; interdisciplinary approach; multidisciplinary; multidrug-resistant Pseudomonas aeruginosa; novel; novel strategies; pathogen; pathogenic bacteria; periplasm; prevent; programs; receptor; recruit; resistant Shigella; small molecule; small molecule libraries; structural biology; targeted treatment; therapeutic development; therapeutic target; therapy development; treatment strategy

PROJECT SUMMARY/ ABSTRACT: The rise of antibacterial resistance highlights the urgent need to develop new effective strategies to combat antibiotic-resistant infections. Ubiquitously, Gram-negative bacterial pathogens assemble extracellular fibers, termed chaperone-usher pathway (CUP) pili, that are critical for the pathogen's ability to cause infections by recognizing and colonizing different host tissues and habitats. Thus, therapeutics targeting the assembly of these fibers hold promise in their potential to result in much needed alternatives for the treatment of multidrug- resistant Gram-negative pathogens. Among these pathogens are those designated as “Urgent Threats” carbapenem-resistant Acinetobacter and carbapenem-resistant Enterobacteriaceae (CRE), as well as “Serious Threats” drug-resistant Campylobacter, extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, multidrug-resistant Pseudomonas aeruginosa, drug-resistant Salmonella, Shigella, and Bordetella pertussis. In each CUP pilus system, a designated periplasmic chaperone and an outer-membrane (OM) usher protein work together to assemble thousands of structural subunits into each final pilus structure. Most CUP pili are also tipped by adhesins that specifically recognize receptors in host tissues. We have made considerable progress towards understanding the remarkably complex mechanisms of pilus assembly. Building on our extensive experience and expertise in CUP pilus biogenesis and in the development of rational therapies targeting CUP pili, this proposal seeks to develop novel antibiotic-sparing therapies targeting the OM ushers using multidisciplinary approaches including bacteriology, chemical biology, medicinal chemistry, structural biology and immunology. Based on the structural characterizations and the dynamic nature of these multi-domain usher proteins, we will rationally develop small molecule usher inhibitors and pore openers by trapping specific conformational states (Aim 1). Usher inhibitors will disarm bacterial virulence factors, whereas pore openers will increase permeability of existing antibiotics into bacterial outer membranes. In addition, we will develop monoclonal antibodies that inactivate usher, thus preventing pilus biogenesis and infection (Aim 2). While our first two aims will concentrate on two of the most studied pilus systems (type 1 and P pili), Aim 3 will expand our studies of ushers in Acinetobacter, Campylobacter, P. aeruginosa, Salmonella, Shigella, and B. pertussis. Collectively, we plan to develop rational therapies against multiple antibiotic-resistant Gram-negative bacterial pathogens. These developments, together with other novel strategies proposed in our multidisciplinary U19 program, will work synergistically to act as efficient antibiotic-sparing therapeutics by blocking usher and adhesin functions. Moreover, the usher pore openers developed in this proposal will increase OM permeability, further alleviating antibiotic resistance in Gram-negative pathogens and allowing us to repurpose existing drugs to enhance the current antibiotic arsenal. Thus, successful developments in these directions will be potentially transformative in combating antibiotic resistance.

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