Discovery of antibiotics active against multidrug resistant bacteria

发现对多重耐药细菌具有活性的抗生素

• 批准号: 8866795
• 负责人: Roberto G. Kolter
• 金额: $ 25.43万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-10 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8866795
• 关键词: Actinobacteria class; Actinomycetales; Agar; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Biological; Biological Assay; Coculture Techniques; Color; Communicable Diseases; Communities; Complex; Conditioned Culture Media; Culture Media; Culture Techniques; Development; Diffuse; Environment; Evolution; Exhibits; Glean; Goals; Growth; History of Medicine; Human; Individual; Infection; Klebsiella pneumonia bacterium; Life; Liquid substance; Methods; Mind; Minor; Multi-Drug Resistance; Nature; Nuclear Magnetic Resonance; Nutrient; Production; Resistance; Ribosomal RNA; Sampling; Sepharose; Source; Staphylococcus aureus; Techniques; Testing; Therapeutic Agents; Time; antimicrobial; base; carbapenem resistance; clinically relevant; genome sequencing; high throughput screening; insight; interest; killings; liquid chromatography mass spectrometry; methicillin resistant Staphylococcus aureus; method development; multi-drug resistant pathogen; novel; novel strategies; pathogen; pathogenic bacteria; public health relevance; research study; resistant strain; small molecule

 DESCRIPTION (provided by applicant): The discovery of antibiotics and their development into therapeutic agents represents one of the most important advances in the history of medicine. However, the evolution of antibiotic resistance is greatly limiting antibiotic usefulness The specter of a post-antibiotic era looms heavy in the field of infectious diseases. Thus, there is an urgent need new antibiotics that are effective against important human pathogens that are now resistant to most, if not all, commonly used antibiotics. Bacteria from the order Actinomycetales have been the most important source of antibiotics. Yet, while the sequenced genomes of these bacteria suggest that there they have the potential to produce many more antibiotic molecules, only a fraction of the predicted molecules have been detected in the lab. In contrast to most culturing techniques that involve only one species, we have discovered that culturing bacteria in multi-species communities stimulates the production of diverse and unique small molecules. With this in mind, in order to stimulate the production of novel antimicrobial compounds, we have developed a method for growing complex multi-species communities over extended periods of time. These communities are grown in an environment that allows them to secrete molecules into a liquid medium that can easily be sampled and assayed for the production of antibiotics that are effective against pathogens such as methicillin resistant Staphylococcus aureus (MRSA) and carbapenem resistant Klebsiella pneumoniae. We specifically propose to develop a large-scale screen for the discovery of novel antibiotic activities produced by Actinomycetes grown as multi-species communities. We also propose to identify and optimize the production of the molecules that display antibiotic activity. These aims will hopefully result in the identification of new antibiotics that are effective against currently problematic multi-drug resistant pathogens.

 描述(由申请人提供)：抗生素的发现及其发展成为治疗剂是医学史上最重要的进步之一。然而，抗生素耐药性的演变极大地限制了抗生素的使用后抗生素时代的幽灵在传染病领域笼罩着沉重的阴影。因此，迫切需要新的抗生素，以有效地对抗重要的人类病原体，这些病原体现在对大多数(如果不是全部)常用抗生素具有抗药性。放线菌目的细菌一直是抗生素的最重要来源。然而，尽管这些细菌的基因组测序表明，它们有可能产生更多的抗生素分子，但实验室只检测到了预测的分子中的一小部分。与大多数只涉及一个物种的培养技术不同，我们发现在多物种群落中培养细菌可以刺激产生多样化和独特的小分子。考虑到这一点，为了刺激新型抗菌化合物的生产，我们开发了一种在较长时间内培养复杂的多物种群落的方法。这些群落生长在一个允许它们将分子分泌到液体介质中的环境中，这种液体介质可以很容易地采样和检测，以生产对甲氧西林耐药金黄色葡萄球菌(MRSA)和碳青霉烯耐药肺炎克雷伯菌等病原体有效的抗生素。我们特别建议开发一种大规模的筛选，以发现由多物种群落生长的放线菌产生的新的抗生素活性。我们还建议识别和优化显示抗生素活性的分子的生产。这些目标有望导致识别出对目前有效的新抗生素。 存在问题的多重耐药病原体。