Targeting of Regulators as a Promising Approach in the Search for Novel Antimicrobial Agents

Abstract

Since the discovery of penicillin in the first half of the last century, antibiotics have become the pillars of modern medicine for fighting bacterial infections. However, pathogens resistant to antibiotic treatment have increased in recent decades, and efforts to discover new antibiotics have decreased. As a result, it is becoming increasingly difficult to treat bacterial infections successfully, and we look forward to more significant efforts from both governments and the scientific community to research new antibacterial drugs. This perspective article highlights the high potential of bacterial transcriptional and posttranscriptional regulators as targets for developing new drugs. We highlight some recent advances in the search for new compounds that inhibit their biological activity and, as such, appear very promising for treating bacterial infections.

Keywords: antibiotic resistance; bacterial pathogens; gene expression; new antibacterial targets; virulence factors regulation.

Figure 1

Transcription regulation and TRs as new antibacterial targets. Transcription regulation concerns the key events leading to transcription: promoter recognition by RNApol, core promoter melting and transcription initiation, and elongation (top left box). TRs are activators or repressors, and positively (green arrow) or negatively (red hammerhead) modulate these events, causing gene expression variations. Compounds targeting the TFs and inhibiting their function interfere with the expression of the TR regulon. TCSs typically consist of an HK and a RR (schematized in the broken-line box). Upon signal sensing, HK undergoes autophosphorylation, the phosphate group is transferred to the RR, which dimerizes and binds the DNA to regulate transcription (steps 1–5). Compounds targeting TCSs can inhibit the various stages of this process.

Figure 2

Schematic representation of the principal mechanisms of action used by base-pairing regulatory sRNAs and possible targeting strategies through antisense short oligonucleotides. A regulatory sRNA binds one or more target transcripts with or without the assistance of an RNA-binding protein (shown as red circles forming a hexamer associated to the sRNA). This interaction results in either positive or negative modulation of gene expression. Left side of the figure: positive regulation occurs when sRNA binding leads to increased ribosome binding site (RBS, represented by a green oval) accessibility and/or protection of the transcript from RNase (depicted by a pink polygon) processing. Right side of the figure: negative regulation of gene expression takes place when sRNA interaction with the target transcript occludes the RBS, preventing ribosome loading (ribosomes are represented by two grey ovals), and/or promoting RNase-mediated processing. Novel sRNA-targeting molecules (indicated with the symbol “TM” in the figure) could act in principle in several ways, affecting the different steps of sRNA-mediated regulation.