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.

抗生素是上个世纪开发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广泛的细菌耐药性，例如耐甲氧西林金黄色葡萄球菌 (MRSA)，因此需要开发新型抗菌化合物。 Berninamycin A 属于噻唑基肽家族，具有对抗革兰氏阳性菌（包括 MRSA）的活性。目前，伯那霉素生物合成的事件顺序尚不清楚，其在生产生物体中形成的结构要求也是未知的。因此，我们将：1）利用伯尼链霉菌基因簇中的适当酶，从伯尼霉素前肽在体外重组伯尼霉素；2）通过伯尼链霉菌的遗传操作，研究伯尼霉素体内合成的底物结构要求。从这项研究中获得的信息将增加我们对大自然如何构建这些结构独特的杂环分子的了解，并可能导致更有效的药物（尤其是抗生素）的开发。