Development of novel anti-Neisseria gonorrhoeae therapeutic agents

新型抗淋病奈瑟菌治疗剂的开发

• 批准号: 10366965
• 负责人: Daniel Patrick Flaherty
• 金额: $ 78.01万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-12 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366965
• 关键词: Acetazolamide; Address; Adverse effects; Antibiotic Therapy; Antibiotics; Antimicrobial Effect; Anus; Arthritis; Azithromycin; Bacteria; Biochemical; Biological Assay; Birth; Blindness; Carbonic Anhydrase Inhibitors; Case Study; Cells; Centers for Disease Control and Prevention (U.S.); Cephalosporin Resistance; Child; Chronic; Clinical; Computer Models; Crystallization; Data; Development; Dose; Drug Kinetics; Drug-resistant Neisseria Gonorrhoeae; Ectopic Pregnancy; Endocarditis; Enzymes; Evaluation; Exhibits; FDA approved; Future; Generations; Genitourinary system; Goals; Gonorrhea; Healthcare Systems; Human; In Vitro; Infection; Infectious Skin Diseases; Infertility; International; Investigational Drugs; Knowledge; Lead; Left; Ligands; Literature; Microbiology; Modeling; Modification; Mothers; Mus; Neisseria gonorrhoeae; Oral; Orthologous Gene; Pathogenicity; Pelvic Inflammatory Disease; Permeability; Pharmaceutical Chemistry; Pharmacology; Property; Protein Isoforms; Public Health; Regimen; Reporting; Resistance; Safety; Sexually Transmitted Diseases; Societies; Structure; Superbug; Surveillance Program; Testing; Therapeutic; Therapeutic Agents; Tissues; Urine; Validation; World Health; World Health Organization; analog; antimicrobial; antimicrobial drug; base; carbonate dehydratase; clinical application; combat; commensal bacteria; design; drug candidate; drug development; drug repurposing; dysbiosis; exhaustion; gut microbiota; improved; in vivo; in vivo evaluation; inhibitor; innovation; lead optimization; mouse model; new therapeutic target; next generation; novel; novel strategies; pathogen; pathogenic bacteria; resistance mechanism; resistant strain; scaffold; small molecule; structural biology; therapeutic target; urogenital tract; vaginal microbiota

Project Abstract: Gonorrhea is a sexually transmitted disease caused by the bacterial pathogen Neisseria gonorrhoeae that colonizes urogenital, anal, and nasopharyngeal tissues. Locally in the United States the Centers for Disease Control and Prevention (CDC) reported a 67% increase of gonorrhea cases between 2013 – 2017 with >550,000 cases in 2017 alone. N. gonorrhoeae wreaks havoc on world health care systems causing pelvic inflammatory disease, infertility and ectopic pregnancies. The bacteria can also be transmitted from mother to child during birth and lead to blindness. If left untreated N. gonorrhoeae can cause gonococcemia resulting in skin infection, arthritis or endocarditis. Pathogenic gonorrhea strains are increasingly resistant to common front-line antibiotics. The WHO surveillance program reports resistance to most available antibiotics. Rampant resistance has caused the CDC and the World Health Organization each to classify N. gonorrhoeae as a superbug and a future with an untreatable gonococcal infection is a real possibility. Thus, there is significant unmet need to identify novel targets and molecules with therapeutic potential. Studies proposed in this application build upon discoveries that FDA- approved carbonic anhydrase inhibitors (CAIs), such as acetazolamide and ethoxzolamide, display potent antimicrobial activity, in an applicable clinical range, against N. gonorrhoeae. CAIs, and analogs we have designed, also have no antimicrobial effect on commensal bacteria reducing the potential for problematic dysbiosis caused by antibiotic treatment. We have shown that the molecules exhibit their antibiotic effect by inhibiting the carbonic anhydrase from N. gonorrhoeae and have validated N. gonorrhoeae carbonic anhydrase (NgCA) as a viable anti-gonococcal therapeutic target. Our team has improved the potency of the CAI-based inhibitors from 4 µg/mL to 0.5 µg/mL. This proposal will continue lead optimization of CAI-based analogs using structure-based design while incorporating modifications to improve permeability into the Gram-negative cell. Molecules will be assessed in in vitro antimicrobial assays and prioritized analogs will progress to in vitro pharmacokinetic (PK) and pharmacologic profiling. Finally, top performing analogs will be assessed for in vivo efficacy in various gonorrhea mouse models as well evaluated the in safety and pharmacokinetic assay to support future lead selection and investigational new drug enabling studies.

项目摘要： 淋病是一种由细菌病原体淋病引起的性传播疾病 在泌尿生殖器，肛门和鼻咽组织中殖民。在美国本地疾病中心 对照与预防（CDC）报告说，2013 - 2017年之间的淋病病例增加了67％，> 550,000 仅2017年的案件。 N. Gonorrhoeae对世界医疗保健系统造成了严重破坏，导致骨盆炎症 疾病，不育和生态妊娠。细菌也可以从母亲传播到孩子 出生并导致失明。如果未治疗的淋病猪笼草可引起淋球菌，导致皮肤感染， 关节炎或心内膜炎。致病性淋病菌株越来越抗性对普通前线抗生素具有抵抗力。 WHO监视计划报告了对大多数可用抗生素的抵抗力。阻力猖ramp 疾病预防控制中心和世界卫生组织各自将淋病。 不可治疗的淋球菌感染是实际的可能性。那是确定新目标的巨大不满意 和具有治疗潜力的分子。该应用中提出的研究基于FDA-的发现 批准的碳酸酐酶抑制剂（CAI），例如乙酰唑胺和乙氧醇胺，表现出有效的 抗菌活性，在适用的临床范围内针对淋病链球菌。 CAI和类似物我们有 设计的，也没有对共生细菌的抗菌作用，降低了问题的潜力 抗生素治疗引起的营养不良。我们已经表明，该分子通过 抑制淋病链球菌的碳赤霉素，并验证了淋病链球菌碳赤霉素蛋白酶 （NGCA）是一个可行的抗多年局治疗靶标。我们的团队提高了基于CAI的效力 从4 µg/ml至0.5 µg/ml的抑制剂。该提案将继续使用使用CAI的类似物来继续优化 基于结构的设计，同时结合了改善渗透性为革兰氏阴性细胞的修饰。 分子将在体外抗菌评估中进行评估，优先类似物将进展到体外 药代动力学（PK）和药理学分析。最后，将评估最高表现类似物的体内 在各种淋病小鼠模型中的功效，以及对安全性和药代动力学测定的评估 支持未来的铅选择和研究新药促成研究。