NEW ANTIBIOTICS--ISOLATION, SYNTHESIS, AND EVALUATION

新抗生素——分离、合成和评估

• 批准号: 2059961
• 负责人: Lester A. Mitscher
• 金额: $ 20.95万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-09-01 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2059961
• 关键词: Retroviridae; antiAIDS agent; antibiotics; chemical structure function; drug design /synthesis /production; drug screening /evaluation; human immunodeficiency virus; mass spectrometry; medicinal plants; nuclear magnetic resonance spectroscopy; plant extracts; polymerase chain reaction; quinoline; tissue /cell culture

The goal of this research is to study the antiinfective agents present in unusual sources, notably higher plant extracts (and of molecules inspired by them), in order to discover new chemical entities with novel modes of action and to determine their potential for use in human medicine. Novel antibiotics are specially sought for the treatment of troublesome viral infections against which contemporary antibiotics are not fully satisfactory because of toxicity, low potency, narrow spectrum, resistance, poor pharmacokinetics, or the like. Central to this effort is the exploration of extracts of suitable botanically identified plants (including those with a folkloric reputation for use as antiinfectives), extraction, screening in vitro against HIV and BIV viruses, bioassay directed fractionation, physico-chemical structure determination, synthesis of analogs (where indicated for structural clarification, preparation of substantial quantities for evaluation, optimization of activity, etc.), evaluation of in vitro antiinfective spectrum in comparison with established agents, and in vivo evaluation in infected experimental animals for the most likely candidates. The latter is done off-site by pharmaceutical firms possessing the special facilities and expertise for this work. Investigation of the molecular mode of action of the quinolones and their interaction with DNA and DNAgyrase was notably successful in earlier versions of this application and these studies will be continued. The fluoroquinolones are among the most widely investigated contemporary antibiotics. Six are marketed in the US, another dozen are approaching marketing decisions and many more are less advanced. One of the quinolones prepared in an earlier version of this grant (levoxacin) is notably active against bacteria causing death to HIV sufferers and is under clinical trial in Japan and the US. We have elaborated and are testing successfully a theory of the molecular mode of action of these agents and this theory is guiding successful design of new chemical entities. Further examination of this theory is proposed as is extension to possible application against the fungal and mammalian enzymes so as to extend or shift the spectrum of contemporary quinolones to include other organisms dangerous to HIV sufferers and to the treatment of cancer. Alternative proposals to rationalize the molecular mode of action of quinolones are also under investigation. Attempts to broaden these investigations to mammalian DNA topoisomerase II are also in progress. The need for modern screening activity is particularly pressing as pressure on tropical biota, alternate land use schemes, and other societal changes in the Third World countries make tropical species and indigenous medical systems increasingly vulnerable.

这项研究的目的是研究存在于 不寻常的来源，尤其是植物提取物（和启发的分子的提取物） 通过他们），为了发现具有新型模式的新化学实体 行动并确定其在人类医学中使用的潜力。小说 特别寻求抗生素治疗麻烦的病毒 当代抗生素不完全的感染 由于毒性，低效力，狭窄的频谱，令人满意 抗性，药代动力学差。这项努力的核心是 探索合适的植物植物提取物 （包括那些以用作反感染的民俗声誉的人）， 提取，对HIV和BIV病毒的体外筛查，生物测定 定向分馏，物理化学结构确定， 类似物的合成（在其中指示结构澄清， 准备大量用于评估，优化 活动等），评估体外抗探测光谱中的评估 与既定剂和感染的体内评估进行比较 最可能候选人的实验动物。后者完成了 拥有特殊设施的制药公司的场地和 这项工作的专业知识。 研究喹诺酮及其分子作用模式 与DNA和dnagyrase的相互作用在早期尤其成功 该应用程序的版本和这些研究将继续。这 氟喹诺酮是最广泛调查的当代人之一 抗生素。六个在美国销售，另外十几个正在接近 营销决策和更多的决策不那么先进。奎诺酮之一 在该赠款的早期版本中准备（Levoxacin）非常活跃 反对细菌导致艾滋病毒患者死亡，并处于临床状态 在日本和美国的审判。我们已经详细阐述并正在成功测试 这些药物的分子作用方式的理论和该理论 正在指导新化学实体的成功设计。进一步检查 提出了这一理论，因为扩展到可能的应用 真菌和哺乳动物酶，以扩展或移动 当代奎诺酮包括对艾滋病毒危险的其他生物 患者和治疗癌症。替代建议 合理化喹诺酮的分子作用方式也在 调查。试图将这些调查扩展到哺乳动物DNA 拓扑异构酶II也正在进行中。 对现代筛查活动的需求特别紧迫 热带生物群，替代土地使用方案和其他社会的压力 第三世界国家的变化是热带物种和土著物种 医疗系统越来越脆弱。