Development of novel anti-Neisseria gonorrhoeae therapeutic agents

新型抗淋病奈瑟菌治疗剂的开发

基本信息

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
项目类别：
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

项目摘要

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：淋病是一种由淋病奈瑟菌引起的性传播疾病定植于美国疾病中心的泌尿生殖、肛门和鼻咽组织。控制与预防 (CDC) 报告称，2013 年至 2017 年间，淋病病例增加了 67%，超过 550,000 例仅 2017 年就有淋病奈瑟菌病例对世界卫生保健系统造成严重破坏，导致盆腔炎。疾病、不孕症和宫外孕期间，细菌也可以从母亲传染给孩子。如果不及时治疗，淋病奈瑟菌可能会导致淋球菌血症，从而导致皮肤感染，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。世界卫生组织监测计划报告说，大多数可用抗生素都出现了耐药性。美国疾病控制与预防中心 (CDC) 和世界卫生组织均将淋病奈瑟菌归类为超级细菌，并认为其未来将面临巨大的威胁。因此，确定新靶标的需求存在重大未得到满足的可能性。以及具有治疗潜力的分子。本申请中提出的研究建立在FDA-的发现之上。批准的碳酸酐酶抑制剂 (CAI)，例如乙酰唑胺和乙恶唑胺，显示出有效的作用在适用的临床范围内，针对 CAI 和我们拥有的类似物具有抗菌活性。设计，对共生细菌也没有抗菌作用，减少了出现问题的可能性我们已经证明，这些分子通过抗生素治疗引起的菌群失调。抑制淋病奈瑟菌碳酸酐酶并验证淋病奈瑟菌碳酸酐酶 (NgCA) 作为可行的抗淋球菌治疗靶点，我们的团队提高了基于 CAI 的效力。抑制剂从 4 µg/mL 到 0.5 µg/mL 该提案将继续使用基于 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革兰氏阴性细胞的渗透性。分子将在体外抗菌测定中进行评估，优先类似物将进展到体外最后，将评估表现最佳的类似物的体内药代动力学 (PK) 和药理学分析。在各种淋病小鼠模型中的疗效以及安全性和药代动力学测定中的评估支持未来的先导药物选择和研究性新药启用研究。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evaluation of 1,3,4-Thiadiazole Carbonic Anhydrase Inhibitors for Gut Decolonization of Vancomycin-Resistant Enterococci.

1,3,4-噻二唑碳酸酐酶抑制剂对万古霉素耐药肠球菌肠道去定植的评价。

DOI：
发表时间：
2023-04-13
期刊：
影响因子：
4.2
作者：
Abutaleb, Nader S;Shrinidhi, Annadka;Bandara, Aloka B;Seleem, Mohamed N;Flaherty, Daniel P
通讯作者：
Flaherty, Daniel P

Structural Characterization of Thiadiazolesulfonamide Inhibitors Bound to Neisseria gonorrhoeae α-Carbonic Anhydrase.

与淋病奈瑟菌α-碳酸酐酶结合的噻二唑磺酰胺抑制剂的结构表征。

DOI：
发表时间：
2023-01-12
期刊：
影响因子：
4.2
作者：
Marapaka, Anil Kumar;Nocentini, Alessio;Youse, Molly S;An, Weiwei;Holly, Katrina J;Das, Chittaranjan;Yadav, Ravi;Seleem, Mohamed N;Supuran, Claudiu T;Flaherty, Daniel P
通讯作者：
Flaherty, Daniel P

Inhibition of pathogenic bacterial carbonic anhydrases by monothiocarbamates.

单硫代氨基甲酸盐抑制病原细菌碳酸酐酶。

DOI：
发表时间：
2023-12
期刊：
影响因子：
5.6
作者：
Giovannuzzi, Simone;Marapaka, Anil Kumar;Abutaleb, Nader S;Carta, Fabrizio;Liang, Hsin;Nocentini, Alessio;Pisano, Luigi;Seleem, Mohamed N;Flaherty, Daniel P;Supuran, Claudiu T
通讯作者：
Supuran, Claudiu T