Structural Basis of Transcription Inhibition by CBR Hydroxamidines and CBR Pyrazoles

Yu Feng, David Degen, Xinyue Wang, Matthew Gigliotti, Shuang Liu, Yu Zhang, Deepankar Das, Trevor Michalchuk, Yon W. Ebright, Meliza Talaue, Nancy Connell, Richard H. Ebright

Research output: Contribution to journalArticle

Abstract

Summary 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 a CBR pyrazole 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.

Original languageEnglish (US)
Article number3215
Pages (from-to)1470-1481
Number of pages12
JournalStructure
Volume23
Issue number8
DOIs
StatePublished - Aug 7 2015
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Feng, Y., Degen, D., Wang, X., Gigliotti, M., Liu, S., Zhang, Y., Das, D., Michalchuk, T., Ebright, Y. W., Talaue, M., Connell, N., & Ebright, R. H. (2015). Structural Basis of Transcription Inhibition by CBR Hydroxamidines and CBR Pyrazoles. Structure, 23(8), 1470-1481. [3215]. https://doi.org/10.1016/j.str.2015.06.009