Targeting bacterial RNA polymerase σ70 for development of broad-spectrum antisense antibacterials

Bacterial DNA-dependent RNA polymerase (RNAP) is the central enzyme among the progress of transcription. The ubiquity, structural and functional similarities among different bacterial species make it an attractive target for developing protein-level anti-RNAP bactericidal agents with broad spectrum. However, the practical value of RNAP inhibitors is limited by an extensively observed single mutation in rpoB gene (encoding the β subunit of RNAP), resulting in completely resistant strains. Antisense antibacterials (also called RNA silencers in bacteria) may present an unusual opportunity for developing broad-spectrum sequence-selective nucleic acid based therapeutics. This review will first present a brief state of knowledge on progress and problems in targeting RNAP. Special emphasis will then be given to introduce the advantageous features of RNAP σ70 as a potential target for broad-spectrum antisense inhibition. Characteristics of the antisense antibacterial strategy (including antisense mechanism, basic chemistry involved in nucleic acid analogs, their anti-infection applications in vitro and in vivo) will also be thoroughly described. Notably, our exploration on targeting σ70 gene in gram-negative and gram-positive bacteria respectively for realization of broad-spectrum antisense bactericidal effect will be elaborated on. This firstly demonstrates peptide nucleic acid (PNA)-peptide conjugate as a successful example of broad-spectrum antisense antibacterial. At the end, we will also highlight a few promising targets and delivery strategies that favor the possible development of broad-spectrum antisense antibacterials.