Mechanism of Antibiotic Resistance by Nascent Peptides

描述(申请人提供)：新生多肽是在核糖体蛋白质生物合成的早期阶段，从肽基转移酶反应中心出现的短氨基酸序列。原核生物中的一些新生多肽含有特殊的序列基序，作用于顺式作用，并通过涉及核糖体停滞的机制来调节抗生素耐药基因的表达。这项拟议的研究将为新生多肽在核糖体出口通道中诱导抗生素耐药性的结构基础奠定基础。该研究计划涉及使用结合合成有机化学、生物化学和结构生物学的多学科方法。我们将合成特定的新生多肽序列，并将它们与肽基转移酶抑制剂共价连接，以便将它们输送到肽基转移酶反应中心和核糖体出口隧道进行分析。我们将在原子分辨率下定义这些序列基序与出口隧道和特定抗生素相互作用的机制和模式。这一结果将为了解抗生素耐药的机制提供基本的见解，并将对合理的药物设计和开发产生广泛的影响。

DESCRIPTION (provided by applicant): Nascent peptides are short amino acid sequences that emerge from the peptidyl transferase reaction center during the early stages of protein biosynthesis in the ribosome. Some nascent peptides in prokaryotes contain special sequence motifs that act in cis and regulate the expression of antibiotic resistance genes by a mechanism that involves ribosomal stalling. The proposed research will establish the structural basis of nascent peptide-induced antibiotic resistance in the exit tunnel of the ribosome. The research plan involves the use of a multidisciplinary approach that combines synthetic organic chemistry, biochemistry and structural biology. We will synthesize specific nascent peptide sequences and covalently link them to peptidyl transferase inhibitors for their delivery into the peptidyl transferase reaction center and the ribosomal exit tunnel for analysis. We will define the mechanism and mode of interactions of these sequence motifs with the exit tunnel and specific antibiotics at atomic resolution. The results will provide fundamental insights into the mechanism of antibiotic resistance and will produce a broad impact on rational drug design and development.