Aminospectinomycin antibacterials for the treatment of antibiotic-resistant gonorrhea and other bacterial STDs

氨基大观霉素抗菌药用于治疗抗生素耐药性淋病和其他细菌性 STD

• 批准号: 9252872
• 负责人: Michelle M. Butler
• 金额: $ 29.68万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-18 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252872
• 关键词: Address; Aminoglycosides; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Azithromycin; Bacteria; Bacterial Proteins; Bacterial Sexually Transmitted Diseases; Binding; Binding Sites; Biological Availability; Case Study; Ceftriaxone; Cell Line; Centers for Disease Control and Prevention (U.S.); Cephalosporins; Cervicitis; Chancroids; Chlamydia Infections; Chlamydia trachomatis; Combined Modality Therapy; Data; Development; Diagnosis; Diagnostic; Disease; Dose; Doxycycline; Drug Kinetics; Drug resistance; Etiology; FDA approved; Goals; Gonorrhea; Hemophilus ducreyi; Human; In Vitro; Infection; Infertility; Intramuscular; Joints; Lead; Lethal Dose 50; Libraries; Mammalian Cell; Mammals; Medical; Modification; Mus; Mycoplasma genitalium; Natural Products; Neisseria gonorrhoeae; New Agents; Oral; Parents; Patients; Pelvic Inflammatory Disease; Pharmaceutical Preparations; Pharmacology; Phase; Poison; Preparation; Prevalence; Protein Biosynthesis; Protein Synthesis Inhibitors; Research; Research Project Grants; Research Proposals; Resistance; Resistance development; Ribosomes; Rights; Route; Safety; Saint Jude Children' s Research Hospital; Series; Sexually Transmitted Diseases; Site; Skin Manifestations; Specificity; Spectinomycin; Structure; Sulfonamides; Syphilis; Testing; Therapeutic; Time; Toxic effect; Toxicology; Translations; Treponema; United States; Urethritis; Viral; analog; co-infection; combat; cost; cytotoxicity; drug discovery; drug-resistant gonorrhea; efficacy evaluation; efficacy study; fluoroquinolone resistance; improved; in vivo; indexing; mouse model; novel; novel therapeutics; pathogen; pre-clinical; resistance frequency; scaffold; small molecule; standard of care; subcutaneous; synergism

Summary/Abstract The overall objective of this project is to test and prioritize aminospectinomycin (amSPC) antibacterials for use as broad-spectrum agents against bacterial sexually transmitted diseases (STDs). The amSPCs, like their parent antibiotic, spectinomycin (SPC), act by inhibiting bacterial protein synthesis by binding to a ribosomal site that is unique among aminoglycosides and other protein synthesis inhibitors. Gonorrhea, caused by the bacterium Neisseria gonorrhoeae, is a STD that afflicts only humans. The disease can be asymptomatic and undiagnosed infections can lead to pelvic inflammatory disease and, ultimately, infertility or may disseminate, causing joint and skin manifestations. Therapeutic options consist of ceftriaxone (250 mg intramuscular in a single dose) plus azithromycin (1 gram orally in a single dose) or doxycycline dosed orally for 7 days. N. gonorrhoeae has acquired resistance to all agents that have been used as therapy, from the 1930s when sulfonamides were used as monotherapy until current times where resistance is developing to ceftriaxone and other extended-spectrum cephalosporins. Infections caused by Chlamydia trachomatis are even more prevalent than gonorrheal infections and, although antibiotic resistance is a smaller problem, people with chlamydial infections are often co-infected with other sexually transmitted bacterial pathogens such as Treponema palladum (syphilis), Haemophilus ducreyi and Mycoplasma genitalium. New small molecule drugs, especially those with synergy with new or existing antibiotics, rendering them useful for combination therapy, are desperately needed and the drug pipeline is very limited. We have discovered a series of novel amSPCs, which are derivatives of SPC, a second-line gonorrhea agent still in use outside of the United States. The structure-activity data available to date demonstrates an excellent (8-32-fold) improvement in in vitro potency compared to SPC and low cytotoxicity against multiple cell lines. The amSPCs represent a safe potential new treatment option for drug resistant gonorrhea and bacterial co-infections. The low oral bioavailability of the amSPCs suggests that they would be administered parenterally, as is standard for aminoglycoside anti- gonorrheal drugs and the current standard-of-care, cefriaxone. The goal of this Phase I research project is to develop the amSPCs as a parenteral therapy for the treatment of bacterial STDs by 1) maintaining potency against N. gonorrhoeae and C. trachomatis, 2) showing efficacy against other bacterial STDs and 3) demonstrating efficacy in a mouse model of gonorrhea. Our strategy is to evaluate and prioritize existing analogs (>100) to demonstrate a broad-spectrum potency against bacterial STD species, maintain low toxicity against mammalian cell lines and maintain or improve in vivo efficacy. In Phase II, we will evaluate the in vivo efficacy of the lead compounds emerging from Phase I in additional murine models of Ng infection and Ng-Ct co-infection and conduct pharmacokinetic and toxicology studies to establish an in vivo safety index and select the final broad-spectrum STD candidate suitable for IND-enabling preclinical GLP studies.

摘要/摘要 该项目的总体目的是测试和优先考虑氨基接受氨基霉素（AMSPC）的抗细菌。 用作针对细菌性传播疾病（STD）的广谱药物。 AMSPC，喜欢 他们的母体抗生素Spectinomycin（SPC）通过与A结合来抑制细菌蛋白的合成作用 在氨基糖苷和其他蛋白质合成抑制剂中独有的核糖体位点。淋病， 由细菌淋病细菌引起的是仅困扰人类的性病。该病可能是 无症状和未诊断的感染会导致骨盆炎症性疾病，最终导致不育症或 可能会传播，导致关节和皮肤表现。治疗方案由头孢曲松组成（250毫克 单剂量的肌肉内）加上阿奇霉素（单剂量1克）或强力霉素口服 7天。 N. Gonorrhoeae已获得对所有被用作治疗药物的药物的抵抗力 1930年代将磺酰胺用作单一疗法时，直到当前耐药性发展为 头孢曲松和其他扩展的头孢菌素。沙眼衣原体引起的感染是 比淋病感染更普遍，尽管抗生素耐药性是一个较小的问题，但人们 与衣原体感染通常与其他性传播的细菌病原体共同感染，例如 treponema palladum（梅毒），嗜血杆菌和支原体生殖器。新的小分子药物， 特别是那些具有新型或现有抗生素协同作用的人，使其可用于联合疗法， 迫切需要，药品管道非常有限。我们发现了一系列新颖的AMSPC， 这是SPC的衍生物，SPC是美国以外仍在使用的二线淋病特工。这 迄今为止可用的结构活性数据表明，体外效力有出色的（8-32倍） 与SPC和低细胞毒性相比多个细胞系。 AMSPC代表了安全的潜力 耐药淋病和细菌共感染的治疗选择。低口服生物利用度 AMSPC建议将其属于肠胃外施用，这是氨基糖苷抗 - 淋病药物和当前护理标准CEFRIAXONE。我研究项目的目标是 开发AMSPC作为肠胃外疗法，以通过1）维持效力来治疗细菌性病 针对淋病链球菌和沙眼梭状芽孢杆菌，2）对其他细菌性病显示疗效，3） 在淋病的小鼠模型中证明了功效。我们的策略是评估并确定现有的优先级 类似物（> 100）证明针对细菌性病物种的广谱效力，保持低毒性 针对哺乳动物细胞系并维持或改善体内功效。在第二阶段，我们将评估体内 NG感染和NG-CT的其他鼠模型中从I期出现的铅化合物的功效 共同感染和进行药代动力学和毒理学研究以建立体内安全指数并选择 最终的广谱性性病候选者适用于促临床前GLP研究。