Chemical synthesis enables biochemical and antibacterial evaluation of streptolydigin antibiotics.
Chemical synthesis enables biochemical and antibacterial evaluation of streptolydigin antibiotics.
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DOI：
10.1021/ja2041964
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发表时间：
2011-08-10
影响因子：
15
通讯作者：
Kozmin, Sergey A.
中科院分区：
文献类型：
--
作者：
Pronin, Sergey V.;Martinez, Anthony;Kuznedelov, Konstantin;Severinov, Konstantin;Shuman, Howard A.;Kozmin, Sergey A.
细菌转录的抑制代表了有效且临床验证的抗感染化疗策略。我们描述了我们的方法的演变，以链霉菌素类抗生素的目标细菌RNA聚合酶（RNAP）。这一努力导致了对streptolydigin、streptolydiginone、streptolic acid和一系列基于streptolydigin的新试剂的合成和生物学评价。随后的RNAP抑制的生物化学评价表明，链霉酸和特特拉姆酸亚基的存在是这类抗生素活性所必需的。此外，我们确定了10，11-dihydrostreptolydigin作为一种新的RNAP靶向剂，它以最长线性序列中15个步骤的高合成效率组装。二氢链霉素抑制三种代表性细菌RNAP，并显示对S.唾液这种全合成抗生素的合成效率的总体增加与显著的抗菌活性相结合，证明了有机合成在实现靶向细菌转录的新化学试剂的设计和全面的体外药理学评价方面的能力。
Inhibition of bacterial transcription represents an effective and clinically validated anti-infective chemotherapeutic strategy. We describe the evolution of our approach to the streptolydigin class of antibiotics that target bacterial RNA polymerases (RNAPs). This effort resulted in the synthesis and biological evaluation of streptolydigin, streptolydiginone, streptolic acid and a series of new streptolydigin-based agents. Subsequent biochemical evaluation of RNAP inhibition demonstrated that the presence of both streptolic acid and tetramic acid subunits was required for activity of this class of antibiotics. In addition, we identified 10,11-dihydrostreptolydigin as a new RNAP-targeting agent, which was assembled with high synthetic efficiency of 15 steps in the longest linear sequence. Dihydrostreptolydigin inhibited three representative bacterial RNAPs and displayed in vitro antibacterial activity against S. salivarius. The overall increase in synthetic efficiency combined with substantial antibacterial activity of this fully synthetic antibiotic demonstrates the power of organic synthesis in enabling design and comprehensive in vitro pharmacological evaluation of new chemical agents that target bacterial transcription.
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影响因子：
5.1
作者：
Carlson, Jacob C.;Li, Shengying;Burr, Douglas A.;Sherman, David H.
通讯作者：
Sherman, David H.
影响因子：
3.3
作者：
KARWOWSKI, JP;JACKSON, M;HUMPHREY, PE
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HUMPHREY, PE
影响因子：
3.3
作者：
BANSAL, MB;DHAWAN, VK;THADEPALLI, H
通讯作者：
THADEPALLI, H
影响因子：
13.8
作者：
Darst, SA
通讯作者：
Darst, SA
影响因子：
3.2
作者：
Horna, Dina H.;Gomez, Cristina;Salas, Jose A.
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