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.
Keywords: Antisense antibacterials, bacterial RNA polymerase, broad spectrum, σ70, Traditional antimicrobial drugs, RNAP Holoenzyme, Pros and Cons, mycobacterial infections, BACTERIAL RNAP, DNA-based nucleic acids
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