Mechanism of Antibiotic Resistance by Nascent Peptides

描述（由申请人提供）：新生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产生的短氨基酸序列。原核生物中的一些新生肽含有特殊的序列基序，这些基序以顺式方式起作用，并通过涉及核糖体延迟的机制调节抗生素抗性基因的表达。本研究将建立核糖体出口通道中新生肽诱导抗生素耐药的结构基础。该研究计划涉及使用多学科方法，结合合成有机化学，生物化学和结构生物学。我们将合成特定的新生肽序列，并将其与肽基转移酶抑制剂共价连接，以便将其传递到肽基转移酶反应中心和核糖体出口通道进行分析。我们将在原子分辨率上定义这些序列基序与出口通道和特定抗生素相互作用的机制和模式。该结果将为抗生素耐药性机制的研究提供基础性的见解，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.