A Riboswitch-Driven Era of New Antibacterials

Abstract

Riboswitches are structured non-coding RNAs found in the 5′ UTR of important genes for bacterial metabolism, virulence and survival. Upon the binding of specific ligands that can vary from simple ions to complex molecules such as nucleotides and tRNAs, riboswitches change their local and global mRNA conformations to affect downstream transcription or translation. Due to their dynamic nature and central regulatory role in bacterial metabolism, riboswitches have been exploited as novel RNA-based targets for the development of new generation antibacterials that can overcome drug-resistance problems. During recent years, several important riboswitch structures from many bacterial representatives, including several prominent human pathogens, have shown that riboswitches are ideal RNA targets for new compounds that can interfere with their structure and function, exhibiting much reduced resistance over time. Most interestingly, mainstream antibiotics that target the ribosome have been shown to effectively modulate the regulatory behavior and capacity of several riboswitches, both in vivo and in vitro, emphasizing the need for more in-depth studies and biological evaluation of new antibiotics. Herein, we summarize the currently known compounds that target several main riboswitches and discuss the role of mainstream antibiotics as modulators of T-box riboswitches, in the dawn of an era of novel inhibitors that target important bacterial regulatory RNAs.

Exploring the structure, function of thiamine pyrophosphate riboswitch, and designing small molecules for antibacterial activity

“…Such mutation reduces the binding affinity of TPP and PTPP by 71 fold and 40 fold, respectively. The reduction in binding of TPP and PTPP with the mutant riboswitch in fungi and bacteria validates that the PT shows antibacterial action by binding with TPP riboswitch (Giarimoglou et al, 2022;Sudarsan et al, 2005). The thiamine analog OTPP oxythiamine reduces the growth rate of Saccharomyces cerevisiae, and in earlier reports, it was assumed that it binds with the enzymes (Tylicki et al, 2003).…”

Multidimensional Applications and Challenges of Riboswitches in Biosensing and Biotherapy

“…The lysine riboswitch is a critical mechanism for monitoring intracellular lysine concentrations. [ 114 ] This riboswitch controls the expression of lysC genes, as well as the production and transportation of lysine and other amino acid precursors. In 2003, the first lysine riboswitch was discovered by Breaker's team, with a KD value of ≈1 µ m .…”

“…This underscores the necessity for stricter and more targeted analogs when aiming for homologous targeting specificity. [ 114 ]…”

“…They can respond to a wide range of endogenous and non-endogenous small molecules, making them versatile tools for various applications. While there have been several key review articles on the applications of riboswitches, with emphasis on bioimaging, gene therapy, drug targets, and food safety detection, [4][5][6][7] a full treatment of the latest advances merits a separate review. This article focuses on riboswitch applications in…”

Small noncoding RNA in Streptococci: From regulatory functions to drug development

“…During the last decades, with rapid development of RNA sequencing technique and bioinformatic analysis tools, numerous streptococcal sRNAs have been identified (Acebo et al., 2012; Krieger et al., 2022; Mann et al., 2012; Tesorero et al., 2013). In addition, RNA target‐based anti‐bacteria therapeutic strategies have also been developed (Giarimoglou et al., 2022; Motika et al., 2020; Panchal & Brenk, 2021). These advances provide us more possibilities to develop novel antistreptococcal antibiotics targeting sRNAs.…”