Targeting Bacterial RNA Polymerase: Promises for Future Antisense Antibiotics Development

Hui      Bai; Ying      Zhou; Zheng      Hou; Xiaoyan      Xue; Jingru      Meng; Xiaoxing      Luo

doi:10.2174/187152611795589708

Abstract

The progress of transcription is synthesized by complex molecules, among which DNA-dependent RNA polymerase (RNAP) is the central enzyme. The prokaryotic RNAP is a large protein composed of core subunits (α2,β and β) and a σ factor that is required for specific recognition of the promoter site and the initiation of transcription. Despite its ubiquity, structural and functional similarities, bacterial RNAPs do not share extensive sequence homology with eukaryotic RNAPs. Bacterial RNAP an attractive target for the development of anti-bacterial drugs as its inactivation would lead to bacterial cell death. This review will present the state of knowledge on the assembly and function of RNAP subunits in bacteria with special focus on insights provided by structural analysis of a key component σ factor. Thorough retrospection has been provided for better understanding of progress and problems in targeting RNAP by traditional chemical compounds. Recent progress using innovative strategies including structural biology and phage based screening, especially the antisense technology, has shed light on developing the first set of macro-molecule RNAP inhibitors. In particular, exploration on targeting RNAP σ70 for realization of broad-spectrum antisense bactericidal effect in gram negative bacteria presents the first successful example of PNA-peptide conjugate showing attractive potential as conventional broad-spectrum antibiotics, in which possible way the antisense antibiotics might develop into to meet the range and type of usage in future health care.

Keywords: Bacterial RNA polymerase, sigma factor, antisense antibiotics, transcription, RNAP, anti-bacterial drugs, phage based screening, antisense technology, complex molecular machine, RNAP inhibitors, tuberculosis, single-step resistance mutations in the target rpoB, Rifs, antisense inhibition, Holoenzyme