Targeting a novel regulatory RNA with novel antibiotics

对抗生素的耐药性正在成为公共卫生的主要威胁，我们正面临着一个可用的风险， 抗生素可能不再足以治疗传染病。迫切需要 获得新的抗菌化合物，并开发生产这种化合物的新方法， 化合物.本研究的目的是开发新的抗菌剂，特异性结合到 抗终止子元件，并抑制抗终止，从而抑制细菌细胞生长。 我们已经在细菌RNA中鉴定出一种新的调节元件，即T盒系统抗终止子， 抗菌药物发现的理想靶点。这种RNA元件广泛分布于革兰氏阳性 细菌，其中必需氨酰-tRNA合成酶（阿尔斯）基因的表达需要它。 T盒功能的抑制导致细菌细胞生长的抑制，从而验证了该元件作为细菌生长的靶标。 抗菌剂。我们的假设是，提出的新类别的恶唑烷酮和相关的 化合物可以开发成新的抗菌剂，T盒抗终止系统 为抗菌作用提供了独特的靶点，并降低了产生耐药性的可能性。 我们的初步结果表明：a）这类新的恶唑烷酮的主要成员结合 具有低微摩尔至纳摩尔亲和力和对独特RNA的良好选择性的抗终止子RNA 结构; B）前导恶唑烷酮与tRNA竞争结合抗终止子RNA; c）前导恶唑烷酮 对革兰氏阳性菌具有抗菌活性;和d）先导化合物抑制转录 体外抗终止。 具体目标是：1）合成和设计新类别的恶唑烷酮和相关化合物;2） 测定对抗终止子模型RNA的亲和力并测定新化合物的抗菌活性：和 3)确认具有抗菌活性的化合物的作用方式。构效关系 (SAR)根据目标2和3确定的，将用于迭代的化合物改进， 分子建模，NMR溶液结构研究和定量SAR分析，以指导设计 化合物.

Resistance to antibiotics is becoming a major threat to public health and we are facing a risk that available antibiotics may no longer be adequate for treatment of infectious diseases. There is a compelling need for obtaining new antibacterial compounds, and for developing new methods for the production of such compounds. The goal of this study is to develop novel antibacterial agents that specifically bind to the antiterminator element of T box RNAs and inhibit antitermination, thereby inhibiting bacterial cell growth. We have identified a novel regulatory element in bacterial RNA, the T box system antiterminator, that is an ideal target for antibacterial drug discovery. This RNA element is widely distributed in Gram-positive bacteria, where it is required for expression of essential aminoacyl-tRNA synthetase (aaRS) genes. Inhibition of T box function results in inhibition of bacterial cell growth, validating this element as a target for antimicrobial agents. Our hypothesis is that the proposed new classes of oxazolidinones and related compounds can be developed into novel antibacterial agents and that the T box antitermination system provides a unique target for antibacterial action with decreased probability of development of resistance. Our preliminary results demonstrate that: a) lead members of this new class of oxazolidinones bind antiterminator RNA with low micromolar to nanomolar affinities and good selectivity for a unique RNA structure; b) lead oxazolidinones compete with tRNA binding to antiterminator RNA; c) lead oxazolidinones have antibacterial activity against Gram-positive bacteria; and d) a lead compound inhibits transcription antitermination in vitro. Specific Aims are: 1) Synthesize and design new classes of oxazolidinones and related compounds;2) Determine affinity for antiterminator model RNA and determine antibacterial activity of new compounds: and 3) Confirm the mode of action of compounds with antibacterial activity. The structure activity relationships (SAR) determined from Aims 2 and 3 will be used in iterative rounds of compound improvement utilizing molecular modeling, NMR solution structure studies and quantitative SAR analysis to guide the design of compounds.