抗生素（E）-3-（3-羧基苯基）-2-（4-氰基苯乙烯基）喹唑啉-4（3H）-酮的发现。
Discovery of antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one.
作者信息
Bouley Renee, Kumarasiri Malika, Peng Zhihong, Otero Lisandro H, Song Wei, Suckow Mark A, Schroeder Valerie A, Wolter William R, Lastochkin Elena, Antunes Nuno T, Pi Hualiang, Vakulenko Sergei, Hermoso Juan A, Chang Mayland, Mobashery Shahriar
机构信息
Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
出版信息
J Am Chem Soc. 2015 Feb 11;137(5):1738-41. doi: 10.1021/jacs.5b00056. Epub 2015 Feb 2.
Abstract
In the face of the clinical challenge posed by resistant bacteria, the present needs for novel classes of antibiotics are genuine. In silico docking and screening, followed by chemical synthesis of a library of quinazolinones, led to the discovery of (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one (compound 2) as an antibiotic effective in vivo against methicillin-resistant Staphylococcus aureus (MRSA). This antibiotic impairs cell-wall biosynthesis as documented by functional assays, showing binding of 2 to penicillin-binding protein (PBP) 2a. We document that the antibiotic also inhibits PBP1 of S. aureus, indicating a broad targeting of structurally similar PBPs by this antibiotic. This class of antibiotics holds promise in fighting MRSA infections.
摘要
面对耐药细菌带来的临床挑战，目前对新型抗生素的需求是切实存在的。通过计算机辅助对接和筛选，随后对喹唑啉酮文库进行化学合成，发现了（E）-3-（3-羧基苯基）-2-（4-氰基苯乙烯基）喹唑啉-4（3H）-酮（化合物2），它是一种在体内对耐甲氧西林金黄色葡萄球菌（MRSA）有效的抗生素。功能试验证明，这种抗生素会损害细胞壁生物合成，表明化合物2与青霉素结合蛋白（PBP）2a结合。我们证明这种抗生素还能抑制金黄色葡萄球菌的PBP1，表明该抗生素对结构相似的PBPs具有广泛的靶向作用。这类抗生素在对抗MRSA感染方面具有前景。
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