Fungal natural products targeting antimicrobial resistant Mycoplasma genitalium

针对抗菌药物耐药性生殖支原体的真菌天然产品

• 批准号: 10308114
• 负责人: Robert Henry Cichewicz
• 金额: $ 19.41万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-25 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308114
• 关键词: Address; American; Aminoglycosides; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Attention; Awareness; Azithromycin; Bacteria; Biological Assay; Biology; Breathing; Cells; Centers for Disease Control and Prevention (U.S.); Cephalosporins; Cervicitis; Chlamydia trachomatis; Clinical; Colistin; Collection; Communicable Diseases; Data; Development; Diagnosis; Diagnostic tests; Doxycycline; Educational workshop; Effectiveness; Endometritis; Exhibits; FDA approved; Folic Acid; Foundations; Fractionation; Future; Geography; Goals; Growth; Health; Human; In Vitro; Infection; Infertility; Inflammation; Investigation; Lead; Left; Libraries; Macrolide-resistance; Mammalian Cell; Measures; Membrane; Mollicutes; Moxifloxacin; Mutation; Mycoplasma genitalium; Natural Products; Natural Products Chemistry; Neisseria gonorrhoeae; Nonspecific urethritis; Organism; Pain; Parasites; Patients; Pelvic Inflammatory Disease; Peptidoglycan; Pharmaceutical Preparations; Population; Population Study; Populations at Risk; Premature Birth; Prevalence; Reporting; Resistance; Resistance development; Resources; Rifampin; Role; Safety; Sampling; Sexual Transmission; Sexually Transmitted Diseases; Site; Source; Specimen; Spectinomycin; Sterility; Structure; Sulfonamides; Taxonomy; Testing; Therapeutic; Toxic effect; Trimethoprim; United States; Woman; Work; antimicrobial; bactericide; base; beta-Lactams; bioactive natural products; counterscreen; drug discovery; effective therapy; emerging pathogen; experimental study; fungus; high risk; high risk population; in vitro testing; inhibitor; men; men who have sex with men; novel; novel therapeutics; pathogen; pathogenic bacteria; quinolone resistance; reproductive tract; resistant strain; scaffold; sensor; skills; success; treatment choice; welfare

Sexually transmitted infections are a worldwide health concern, with over a million infections acquired each day. Mycoplasma genitalium is an important sexually transmitted bacterial pathogen, associated with severe upper reproductive tract sequelae in women and lower genital tract infections in both men and women. In November 2019, the CDC convened a workshop focused on STD-related pelvic inflammatory diseases in which M. genitalium was recognized as a key, but understudied, emerging pathogen that threatens the safety and welfare of the American public. The prevalence of M. genitalium in the US is higher than Neisseria gonorrhoeae and Chlamydia trachomatis in a growing number of settings with resistance to the recommended first-line treatment, azithromycin, exceeding 50% in many situation and reaching 70-90% in the most-at-risk populations. Alarmingly, resistance to moxifloxacin, recommended for macrolide-resistant strains, is increasingly detected. This spurred the CDC to include M. genitalium on its watch list in the “2019 Antibiotic Resistance Threats in the United States” report. New drugs are needed to target what is clinically evolving into a nearly untreatable pathogen. We hypothesize that fungal natural products are an untapped source of novel antimicrobials that can be used to target M. genitalium and propose to combine our unique expertise in drug discovery and M. genitalium biology (one of only a few labs in the US that studies this fastidious organism) to develop early-stage lead compounds. We will test this hypothesis and work toward providing urgently needed bioactive drug leads through the following three specific aims: (1) test libraries of fungus-derived pure compounds and extracts for inhibition of M. genitalium growth; (2) prioritize bioactive substances, conduct assay-guided purification of inhibitory molecules, and determined their structures; and (3) investigate the activity of bioactive substances against clinical strains, as well as test for resistance development. Specifically, we will use a library of 900 purified fungal natural products, as well as 2,500 extracts produced from taxonomically diverse fungi collected over a wide range of geographical and environmental sites for activity against M. genitalium (strain G37 will be used as the assay sensor strain). Highly active pure compounds that exhibit low levels of toxicity toward human cells will be further tested against a collection of low passage antimicrobial-resistant M. genitalium clinical isolates. Upon characterizing the inhibition profiles of the active compounds as bactericidal or bacteriostatic, the potential for resistance development will be probed. We anticipate delivering 2-3 new bioactive natural-product scaffolds during each year of this R21 investigation with the goal of identifying highly promising molecules that will become the subjects of further lead compound development in the context of future R01 studies. We are unaware of prior focused efforts to systematically mine fungi and their natural products for inhibitors of M. genitalium and we have been highly encouraged by the results of our preliminary studies demonstrating that certain fungal metabolites and extracts exhibit potent inhibitory activities against this difficult-to-treat sexually-transmitted parasite.

性传播感染是全球健康问题，每天收到超过一百万个感染。 支原体生殖器是重要的性传播细菌病原体，与严重的上部有关 女性和女性生殖道感染的生殖遗传后遗症。 2019年11月， 疾病预防控制中心召集了一个针对性与性病相关的骨盆炎症性疾病的研讨会，生殖器分枝杆菌为 被公认为钥匙，但被理解为威胁美国人安全和福利的新兴病原体 民众。美国生殖器分枝杆菌的患病率高于淋病奈瑟氏菌和沙眼衣原体 在越来越多的环境中，对推荐的一线治疗的抵抗力超过了阿奇霉素 在许多情况下，有50％的人在风险最高的人群中达到70-90％。令人震惊的是，对莫西沙星的抗性， 推荐用于抗大花环菌株的菌株，越来越多地检测到。这刺激了CDC包括生殖器。 在“ 2019年美国抗生素抗性威胁”报告中，其观察名单上的报告。需要新药 靶向临床演变成几乎无法治疗的病原体。我们假设真菌天然产品 是一种未开发的新型抗菌剂来源，可用于靶向生殖器。 我们在药物发现和生殖器生物学生物学硕士学位方面的独特专业知识（美国仅有的少数几个研究的实验室之一 这种挑剔的有机体）开发早期铅化合物。我们将检验这个假设，并致力于 通过以下三个特定目的提供急需的生物活性药物的导致：（1）测试库 真菌衍生的纯化合物和提取物，可抑制生殖器分枝杆菌的生长； （2）优先级生物活性 物质，进行评估引导的抑制分子纯化，并确定其结构； （3） 研究生物活性物质对临床菌株的活性，并测试耐药性发展。 具体而言，我们将使用900个纯化的真菌天然产品的库，以及由2500种提取物。 分类学多样化的真菌在各种地理和环境场所收集 针对生殖器分枝杆菌（菌株G37将用作测定传感器应变）。高度活跃的纯化合物 针对低密码的集合，将进一步测试对人类细胞的毒性较低 抗菌抗菌作用分枝杆菌临床分离株。表征活性的抑制曲线 将探测抗抗性或抑制性的化合物。我们 预计在此R21调查的每一年中，将提供2-3个新的生物活性自然产品支架 确定将成为进一步铅化合物主题的高度有希望的分子的目标 在未来R01研究的背景下发展。我们没有意识到先前集中精力的系统挖掘 真菌及其针对生殖器支原体抑制剂的天然产物，结果我们受到了强烈的鼓励 我们的初步研究表明，某些真菌代谢物和提取物提取了有效的抑制 反对这种难以治疗的性传播寄生虫的活动。

项目成果

In Vitro Susceptibility and Resistance of Mycoplasma genitalium to Nitroimidazoles.

• DOI: 10.1128/aac.00006-23
• 发表时间: 2023-04-18
• 期刊: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
• 影响因子: 4.9
• 作者: Wood, Gwendolyn E.;Kim, Caroline M.;Aguila, Laarni Kendra T.;Cichewicz, Robert H.
• 通讯作者: Cichewicz, Robert H.