Probing the Biosynthesis of Thiazolyl Peptide Antibiotic Berninamycin A

噻唑基肽类抗生素伯尼霉素A的生物合成探讨

• 批准号: 8249239
• 负责人: Steven Joseph Malcolmson
• 金额: $ 4.92万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249239
• 关键词: Alanine; Amino Acids; Anabolism; Anti-Bacterial Agents; Antibiotics; Bacterial Infections; Biological; Biological Assay; Development; Disease; Drug Kinetics; Enzymes; Event; Family; Gene Cluster; Gram-Positive Bacteria; Health; Human; In Vitro; Knowledge; Lead; Medical; Medicine; Mutation; Nature; Organism; Peptide Antibiotics; Peptides; Pharmaceutical Preparations; Post-Translational Protein Processing; Process; Production; Property; Reporting; Streptomyces; Therapeutic Agents; analog; bacterial resistance; combat; design; genetic manipulation; improved; in vivo; member; methicillin resistant Staphylococcus aureus; novel; prevent; reconstitution

Antibiotics constitute one of the most effective classes of therapeutic agents developed over the last century; however, the sustained use of these compounds has led to widespread bacterial resistance, such as in methicillin-resistant Staphylococcus aureus (MRSA), necessitating the development of novel antibacterial compounds. Berninamycin A, from the thiazolyl peptide family, has shown activity against Gram-positive bacteria, including MRSA. Currently, the sequence of events comprising the biosynthesis of berninamycin is unknown as are the structural requirements for its formation in the producing organism. We will therefore: 1) reconstitute berninamycin in vitro from the pre-berninamycin peptide, utilizing the appropriate enzymes from the Streptomyces bernensis gene cluster and 2) investigate the substrate structural requirements for berninamycin synthesis in vivo, through genetic manipulation of S. bernensis. The information garnered from this study will increase our knowledge of how Nature constructs these architecturally unique heterocyclic molecules and may lead to the development of more potent medicines, especially antibiotics.

抗生素是上个世纪发展起来的最有效的治疗药物之一；然而，这些化合物的持续使用导致了细菌的广泛耐药性，例如耐甲氧西林金黄色葡萄球菌(MRSA)，这就需要开发新的抗菌化合物。来自噻唑基多肽家族的贝尼阿霉素A对包括MRSA在内的革兰氏阳性细菌显示出活性。目前，组成贝尼阿霉素生物合成的事件序列以及其在生产有机体中形成的结构要求是未知的。因此，我们将：1)利用伯尔尼链霉菌基因簇中合适的酶，在体外从伯尔尼链霉菌前体肽中重组出伯宁霉素；2)通过对伯尔尼链霉菌的遗传操作，研究体内合成伯宁霉素所需的底物结构。从这项研究中获得的信息将增加我们对自然如何构建这些结构独特的杂环分子的知识，并可能导致更有效的药物的开发，特别是抗生素。