Fusidic acid derivatization to enhance entry into Gram-negative pathogens

夫西地酸衍生化以增强进入革兰氏阴性病原体的能力

• 批准号: 9807473
• 负责人: JAMES E KIRBY
• 金额: $ 26.61万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807473
• 关键词: Acinetobacter baumannii; Address; Alcohols; Alkenes; Amines; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Bacterial Infections; Binding; Biological Assay; Cells; Centers for Disease Control and Prevention (U.S.); Cleaved cell; Colistin; Data; Development; Elements; Enterobacteriaceae; Evaluation; Fluorides; Fluorine; Frequencies; Fusidic Acid; Goals; Gram-Negative Bacteria; Human; In Vitro; Infection; Intravenous; Laboratories; Measurement; Medical; Membrane; Metabolic; Methicillin Resistance; Microbiology; Molecular; Multi-Drug Resistance; Mycobacterium tuberculosis; Natural Products; Neisseria gonorrhoeae; Oral; Organism; Penetrance; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasmids; Property; Proteins; Pseudomonas aeruginosa; Publishing; Resistance; Route; Safety; Scheme; Series; Side; Site-Directed Mutagenesis; Staphylococcus aureus; Steroids; Therapeutic; Toxicology; Translations; Work; analog; antimicrobial; base; carbapenem-resistant Enterobacteriaceae; carbapenemase; colistin resistance; cost; emerging antimicrobial resistance; experimental study; fitness; improved; in vivo; innovation; next generation; novel; novel therapeutics; pathogen; pathogenic bacteria; pressure; resistant strain; scaffold; translation assay

Carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa are emerging multidrug-resistant Gram-negative bacterial pathogens. With increasing frequency, they often prove untreatable or treatable only with toxic antimicrobials. Therefore, the CDC now categorizes such organisms in their top antibiotic resistance threat level. New anti-infective strategies are urgently needed. Fusidic acid is a steroid antibiotic that has activity against S. aureus inclusive of methicillin-resistant strains, M. tuberculosis, and N. gonorrhoeae. It also has an excellent safety profile in humans and can be given by both by oral and intravenous routes. However, it does not penetrate the outer membrane of Gram-negative ESKAPE pathogens, and, therefore, these pathogens are resistant to achievable drug levels. However, experiments performed in combination with colistin and other membrane-permeabilizing agents indicate that even the most highly resistant carbapenemase-producing, colistin-resistant Enterobacteriaceae (expressing NDM-1, KPC, VIM, and/or MCR-1) and also A. baumannii and P. aeruginosa are susceptible to this antibiotic, if outer membrane penetration is facilitated. Further, the major circulating resistance elements in S. aureus that bind to and block the fusidic acid target (EF-Tu) are ineffective against Gram-negative pathogens. Further, target modification- based resistance confers a significant fitness cost. Therefore, pre-existing resistance in Gram-negatives is predicted to be negligible, and non-transferable from Gram-positive organisms. Recently so-called eNTRy rules have defined molecular properties that enhance penetrance into Gram-negatives. Based on intrinsically compelling properties of fusidic acid, we propose to use novel retrosynthetic semi-synthesis approaches to apply eNTRy rules during development of fusidic acid analogues, via amine and fluorine substitution. The underlying goal will be to identify analogues that have broad-spectrum activity against both Gram-positive and Gram-negative pathogens and fill a critical medical need. There are no previously published efforts along these lines, and, therefore, the proposed work is both novel and innovative. Importantly, the analogues will be profiled in a series of complementary functional studies. These will include both in vitro and in vivo measurements that will distinguish effects of penetrance and activity; activity spectrum studies; and assessment of metabolic stability; resistance propensity, and toxicology that will help rank compounds for further intensive exploration. The near-term goal of this two-year, exploratory R21 proposal is to address potential of retrosynthetic application of eNTRy rules to identify tractable, potent, broad-spectrum fusidic acid analogues worthy of further exploration.

耐碳青霉烯类肠杆菌科细菌、鲍曼不动杆菌和铜绿假单胞菌 新出现的多重耐药革兰氏阴性细菌病原体。随着频率的增加，他们经常证明 无法治疗或只能用有毒抗菌剂治疗。因此，疾病预防控制中心现在将此类生物体分类为 他们的最高抗生素耐药性威胁级别。迫切需要新的抗感染策略。夫西地酸是一种 类固醇抗生素，对金黄色葡萄球菌（包括耐甲氧西林菌株、结核分枝杆菌、 和淋病奈瑟菌。它对人类也具有出色的安全性，可以通过口服和 静脉途径。然而，它不能穿透革兰氏阴性 ESKAPE 病原体的外膜， 因此，这些病原体对可达到的药物水平具有抵抗力。然而，实验进行于 与粘菌素和其他膜透化剂的组合表明，即使是最高的 产生抗性碳青霉烯酶、粘菌素抗性肠杆菌科（表达 NDM-1、KPC、VIM、 和/或 MCR-1）以及鲍曼不动杆菌和铜绿假单胞菌对这种抗生素敏感，如果外膜 促进渗透。此外，金黄色葡萄球菌中主要的循环耐药元件结合并阻断 夫西地酸靶标（EF-Tu）对革兰氏阴性病原体无效。此外，目标修改—— 基于阻力会带来巨大的健身成本。因此，革兰氏阴性菌中预先存在的耐药性是 预计可以忽略不计，并且不可从革兰氏阳性生物体转移。最近所谓的 eNTRy 规则定义了增强革兰氏阴性菌外显率的分子特性。基于本质 由于夫西地酸具有引人注目的特性，我们建议使用新颖的逆合成半合成方法来 在夫西地酸类似物的开发过程中，通过胺和氟取代应用 eNTRy 规则。这 根本目标是鉴定对革兰氏阳性菌和革兰氏阳性菌均具有广谱活性的类似物。 革兰氏阴性病原体并满足关键的医疗需求。之前没有发布过这些方面的努力 线，因此，拟议的工作既新颖又具有创新性。重要的是，类似物将是 在一系列补充功能研究中进行了描述。这些将包括体外和体内 区分外显率和活性影响的测量；活动谱研究；和 代谢稳定性评估；耐药倾向和毒理学将有助于对化合物进行排名 进一步深入探索。这项为期两年的探索性 R21 提案的近期目标是解决 eNTRy 规则逆合成应用鉴定易处理、有效、广谱夫西地酸的潜力 值得进一步探索的类似物。