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: 10683068
• 负责人: Daniel Patrick Flaherty
• 金额: $ 76.48万
• 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/10683068
• 关键词: Acetazolamide; Address; Adverse effects; Antibiotic Therapy; Antibiotics; Antimicrobial Effect; Anus; Arthritis; Azithromycin; Bacteria; Biochemical; Biological Assay; Biological Availability; Birth; Blindness; Carbonic Anhydrase Inhibitors; Case Study; Cells; Centers for Disease Control and Prevention (U.S.); Cephalosporins; Chronic; Classification; Clinical; Computer Models; Data; Development; Dose; Drug Kinetics; Drug-resistant Neisseria Gonorrhoeae; Ectopic Pregnancy; Endocarditis; Enzymes; Evaluation; Excretory function; 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; Ligand Binding; Literature; Modeling; Modification; Mus; Nasopharynx; Neisseria gonorrhoeae; Oral; Orthologous Gene; Pathogenicity; Pelvic Inflammatory Disease; Permeability; Pharmaceutical Chemistry; Property; Protein Isoforms; Public Health; Regimen; Reporting; Resistance; Safety; Sexually Transmitted Diseases; Societies; Structure; Superbug; Surveillance Program; Testing; Therapeutic; Therapeutic Agents; Tissues; Urine; Validation; Vertical Disease Transmission; World Health; World Health Organization; analog; antimicrobial; antimicrobial drug; carbonate dehydratase; clinical application; combat; commensal bacteria; design; drug candidate; drug development; drug repurposing; dysbiosis; 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; pharmacologic; 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： 淋病是一种由细菌性病原体淋病奈瑟菌引起的性传播疾病 寄生在泌尿生殖器肛门和鼻咽组织上在美国当地， 美国疾病控制和预防中心（CDC）报告称，2013 - 2017年间淋病病例增加了67%，超过55万例 仅2017年的案件。N.淋病对世界卫生保健系统造成严重破坏，引起盆腔炎 疾病、不孕症和宫外孕。这种细菌也可以从母亲传染给孩子， 出生并导致失明。如果不治疗，N。淋病可引起导致皮肤感染的淋球菌血症， 关节炎或心内膜炎。致病性淋病菌株对常见的一线抗生素的耐药性越来越强。 世卫组织监测项目报告了对大多数可用抗生素的耐药性。激烈的抵抗导致 CDC和世界卫生组织各自将N.淋病作为一种超级细菌， 无法治愈的淋球菌感染是真实的可能性。因此，存在显著的未满足的需求，以确定新的目标 和具有治疗潜力的分子。本申请中提出的研究基于FDA- 批准的碳酸酐酶抑制剂（CAIs），如乙酰唑胺和乙氧唑胺，显示出有效的 抗微生物活性，在适用的临床范围内，对N.淋病计算机辅助设计和类似物 设计，也没有抗菌作用，减少潜在的问题， 抗生素治疗引起的生态失调。我们已经证明，这些分子通过以下方式表现出它们的抗生素效应： 抑制N.淋病，并已验证N.淋病碳酸酐酶 （NgCA）作为可行的抗淋球菌治疗靶标。我们的团队已经提高了基于CAI的 抑制剂从4 µg/mL至0.5 µg/mL。该提案将继续使用以下方法对基于CAI的类似物进行优化 基于结构的设计，同时结合修改以提高对革兰氏阴性细胞的渗透性。 分子将在体外抗菌试验中进行评估，优先类似物将在体外进行 药代动力学（PK）和药理学特征分析。最后，将评估表现最好的类似物的体内 在各种淋病小鼠模型中的疗效以及在安全性和药代动力学测定中的评价， 支持未来的先导药物选择和研究性新药启动研究。