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 该项目的总体目标是测试和优先选择氨基环菌素(AmSPC)抗菌药 用作抗细菌性传播疾病(STDS)的广谱制剂。AmSPC，就像 它们的母体抗生素，壮观霉素(SPC)，通过与一种 核糖体部位，在氨基糖苷类和其他蛋白质合成抑制剂中是独一无二的。淋病, 由淋球菌引起的性病是一种只影响人类的性传播疾病。这种疾病可以是 无症状和未诊断的感染可导致盆腔炎，最终导致不孕不育或 可能扩散，引起关节和皮肤表现。治疗方案包括头孢曲松(250毫克 肌肉注射)加阿奇霉素(单次口服1克)或口服多西环素 七天。淋病奈瑟菌对所有用于治疗的药物都产生了抗药性。 20世纪30年代，磺胺类药物被用作单一疗法，直到现在，耐药性正在发展到 头孢曲松和其他超广谱头孢菌素。沙眼衣原体引起的感染有 甚至比淋病更普遍，尽管抗生素耐药性是一个较小的问题，但人们 衣原体感染通常与其他性传播细菌病原体共同感染，如 梅毒螺旋体(梅毒)、杜氏嗜血杆菌和生殖支原体。新的小分子药物， 尤其是那些与新的或现有的抗生素具有协同作用的药物，使其对联合治疗有用， 是迫切需要的，而药物管道非常有限。我们发现了一系列新颖的amSPC， 它们是SPC的衍生品，SPC是一种二线淋病药物，仍在美国以外的地方使用。这个 迄今可获得的构效数据显示，体外效力有极好的(8-32倍)提高 与SPC相比，对多种细胞系具有较低的细胞毒性。AmSPC代表着一种安全的潜在的新 耐药淋病和细菌混合感染的治疗选择。口服生物利用度低 AmSPC建议他们可以非肠道给药，这是氨基糖苷类抗癌药物的标准。 淋病药物和目前的标准护理，头孢曲松。这个第一阶段研究项目的目标是 开发amSPC作为一种非肠道疗法，通过1)保持效力来治疗细菌性性病 抗淋病奈瑟菌和沙眼衣原体，2)对其他细菌性传播疾病有效，3) 在淋病小鼠模型上展示了有效性。我们的战略是评估和优先考虑现有的 类似物(&gt；100)对细菌性STD物种具有广谱效力，保持低毒 抗哺乳动物细胞系，维持或提高体内药效。在第二阶段，我们将评估体内的 从第一阶段出现的先导化合物对附加的Ng感染和Ng-Ct小鼠模型的疗效 并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STD候选药物，适用于IND-Enabling临床前GLP研究。