Bacterial Transcription as a Target for Antibacterial Drug Development

Abstract

SUMMARYTranscription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design.

Protein‐protein interactions as antibiotic targets: A medicinal chemistry perspective

“…Moreover, time‐kill experiments showed each compound killed > 99% of cells in 24 hours. Further, 42 , 44 , and 45 were not cytotoxic toward eukaryotic Saccharomyces cerevisiae at concentrations of 100, 100, and 50 μM, respectively …”

“…This LM binds these hydrophobic sites of ExoI via the LM terminal residues P176 and F177, although only Site A is involved in SSB binding and ExoI stimulation in solution. Mutagenesis of the F177 residue of the peptide has been shown to be lethal to E. coli , leading to preliminary research into SSB as an antibacterial drug target …”

Discovery, properties, and biosynthesis of pseudouridimycin, an antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase

“…In addition to rifamycins, lipiarmycins, and PUM, at least a dozen other classes of antibacterial microbial natural products function as RNAP inhibitors, interacting with at least seven different, largely non-overlapping. binding sites on RNAP [Figure 2; 16, 23, 24, 39 and references therein]). We believe it will be possible to discover yet more novel classes of antibacterial RNAP inhibitors from microbial sources, for example, by employing assays expressly designed to find additional nucleoside-analog RNAP inhibitors [9].…”

Bacterial RNA Polymerase-DNA Interaction—The Driving Force of Gene Expression and the Target for Drug Action

“…Because bacterial RNAP performs essential functions in the cell, and because it differs sufficiently from eukaryotic RNAPs, it is an attractive target for antibiotics (for comprehensive review on the subject, see Ma et al, 2016). Currently, known drugs targeting RNAP can be divided into three groups based on their modes of action (Table 1): (i) those that disrupt RNAP interactions with DNA, RNA or NTPs; (ii) those that interfere with the movement of RNAP mobile elements during nucleotide addition cycle (NAC); and (iii) those that disrupt RNAP interactions with the housekeeping initiation factor, σ 70 .…”