Probing the Biosynthesis of Thiazolyl Peptide Antibiotic Berninamycin A

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），这就需要开发新的抗菌化合物。伯纳德霉素A，来自噻唑基肽家族，已经显示出对革兰氏阳性细菌的活性，包括MRSA。目前，包括贝纳霉素生物合成的事件序列是未知的，其在生产生物体内形成的结构要求也是未知的。因此，我们将：1)利用伯氏链霉菌基因簇中合适的酶，从伯氏链霉菌前肽中体外重组伯氏链霉菌；2)通过对伯氏链霉菌的基因操作，研究伯氏链霉菌体内合成伯氏链霉菌底物的结构要求。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，并可能导致开发更有效的药物，特别是抗生素。

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.