Structural Basis of Transcription Inhibition by CBR Hydroxamidines and CBR Pyrazoles.
Structural Basis of Transcription Inhibition by CBR Hydroxamidines and CBR Pyrazoles.
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DOI：
10.1016/j.str.2015.06.009
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发表时间：
2015-08-04
期刊：
影响因子：
--
通讯作者：
Ebright RH
中科院分区：
文献类型：
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作者：
Feng Y;Degen D;Wang X;Gigliotti M;Liu S;Zhang Y;Das D;Michalchuk T;Ebright YW;Talaue M;Connell N;Ebright RH
CBR羟胺类化合物是通过高通量筛选合成化合物文库发现的细菌RNA聚合酶(RNAP)的小分子抑制剂。CBR吡唑类化合物是通过CBR羟胺类化合物的“支架跳跃”而发现的结构相关的RNAP抑制剂。CBR羟胺类和吡唑类化合物选择性地抑制革兰氏阴性菌的RNAP，并对革兰氏阴性菌表现出选择性的抗菌活性。在这里，我们报道了原型CBR羟胺，CBR703，以及两个CBR吡唑与大肠杆菌RNAP全酶的络合物的晶体结构。此外，我们定义了CBR703的完全耐药性决定因素，证明了CBR703的结合部位和耐药性决定因素不与其他特征RNAP抑制剂的结合部位和耐药性决定因素重叠，表明CBR703与其他特征RNAP抑制剂没有交叉耐药性或表现出最小的交叉耐药性，并表明CBR703与其他RNAP抑制剂联合使用会产生相加的抗菌活性。这一结果为CBR抑制剂作为抗菌药物的结构优化奠定了基础。
CBR hydroxamidines are small-molecule inhibitors of bacterial RNA polymerase (RNAP) discovered through high-throughput-screening of synthetic-compound libraries. CBR pyrazoles are structurally related RNAP inhibitors discovered through “scaffold hopping” from CBR hydroxamidines. CBR hydroxamidines and pyrazoles selectively inhibit Gram-negative bacterial RNAP and exhibit selective antibacterial activity against Gram-negative bacteria. Here, we report crystal structures of the prototype CBR hydroxamidine, CBR703, and two CBR pyrazoles in complex with E. coli RNAP holoenzyme. In addition, we define the full resistance determinant for CBR703, show that the binding site and resistance determinant for CBR703 do not overlap the binding sites and resistance determinants of other characterized RNAP inhibitors, show that CBR703 exhibits no or minimal cross-resistance with other characterized RNAP inhibitors, and show that co-administration of CBR703 with other RNAP inhibitors results in additive antibacterial activities. The results set the stage for structure-based optimization of CBR inhibitors as antibacterial drugs.