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.

总结/摘要 本项目的总体目标是测试和优先考虑氨基壮观霉素（amSPC）抗菌药物， 作为广谱剂用于细菌性传播疾病（STD）。美国特种作战部队 它们的母体抗生素壮观霉素（SPC）通过与细菌蛋白质结合来抑制细菌蛋白质合成， 在氨基糖苷类和其他蛋白质合成抑制剂中是独特的。淋病， 由淋病奈瑟氏菌引起，是一种只折磨人类的性病。这种疾病可以 无症状和未确诊的感染可导致盆腔炎，并最终导致不孕症， 可能扩散，引起关节和皮肤症状。治疗选择包括头孢曲松（250 mg 单剂量肌内注射）加阿奇霉素（单剂量口服1克）或多西环素口服给药 7天。n.淋病已获得耐药性的所有药物已被用作治疗，从 20世纪30年代，磺胺类药物被用作单一疗法，直到目前耐药性正在发展， 头孢曲松和其他广谱头孢菌素。由沙眼衣原体引起的感染是 甚至比淋病感染更普遍，尽管抗生素耐药性是一个较小的问题， 衣原体感染的患者通常与其他性传播的细菌病原体共同感染， 梅毒螺旋体（梅毒）、杜克雷嗜血杆菌和生殖支原体。新的小分子药物， 特别是与新的或现有的抗生素具有协同作用的那些，使它们可用于联合治疗， 而药物供应渠道非常有限。我们已经发现了一系列新颖的amSPC， 它是SPC的衍生物，SPC是一种在美国以外仍在使用的二线淋病剂。的 迄今为止可获得的结构-活性数据证明了体外效力的优异（8 - 32倍）改善 与SPC相比，对多种细胞系的细胞毒性低。amSPC代表了一种安全的潜在新 耐药性淋病和细菌合并感染的治疗选择。口服生物利用度低， amSPC表明它们将被胃肠外给药，如氨基糖苷类抗- 淋病药物和目前的标准治疗头孢曲松。第一阶段研究项目的目标是 开发amSPC作为治疗细菌性STD的胃肠外疗法，通过1）维持效力 对猫背肛螨gonorrhoeae和C.沙眼，2）显示出对其他细菌性STD的功效，和3） 在淋病的小鼠模型中证明了有效性。我们的战略是评估和优先考虑现有的 类似物（> 100），以证明对细菌性STD物种的广谱效力，保持低毒性 抗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 I期研究中出现的先导化合物在其他Ng感染和Ng-Ct小鼠模型中的疗效 进行药代动力学和毒理学研究，以建立体内安全性指数，并选择 最终的广谱STD候选药物，适用于IND临床前GLP研究。