Riboswitches as Drug Targets for Antibiotics

Abstract

Riboswitches reside in the untranslated region of RNA and regulate genes involved in the biosynthesis of essential metabolites through binding of small molecules. Since their discovery at the beginning of this century, riboswitches have been regarded as potential antibacterial targets. Using fragment screening, high-throughput screening and rational ligand design guided by X-ray crystallography, lead compounds against various riboswitches have been identified. Here, we review the current status and suitability of the thiamine pyrophosphate (TPP), flavin mononucleotide (FMN), glmS, guanine, and other riboswitches as antibacterial targets and discuss them in a biological context. Further, we highlight challenges in riboswitch drug discovery and emphasis the need to develop riboswitch specific high-throughput screening methods.

DrugPred_RNA—A Tool for Structure-Based Druggability Predictions for RNA Binding Sites

“…This finding underlines the notation that these promising targets for new antibiotics could be addressed with drug-like ligands. 3 , 12 , 21 Further, also in the ribosomal binding site set, druggable pockets were contained ( Table S4 ). These predictions can help to direct efforts when targeting the ribosome for the development of drugs to overcome the looming antibiotic crisis.…”

“… 9 , 10 Riboswitches, which are noncoding RNA structures in the 5′ untranslated region and regulate gene expression through metabolite binding, are new RNA drug targets for antibiotics. 11 , 12 For example, compounds binding to the flavin mononucleotide (FMN) riboswitch, e.g., ribocil and 5FDQD, have been shown to kill bacteria ( Figure 1 ). 13 , 14 Riboflavin is known to bind to both the FMN riboswitch and riboflavin kinase.…”

DrugPred_RNA – Structure-Based Druggability Predictions for RNA Binding Sites

“…This finding underlines the notation that these promising targets for new antibiotics could be addressed with drug-like ligands. 3,12,20 Further, also in the ribosomal binding site set druggable pockets were contained (Table S3). These predictions can help to direct efforts when targeting the ribosome for the development of drugs to overcome the looming antibiotic crisis.…”

“…9,10 Riboswitches, which are noncoding RNA structures in the 5'untranslated region and regulate gene expression through metabolite binding are new RNA drug targets for antibiotics. 11,12 For example, compounds binding to the flavin mononucleotide (FMN) riboswitch, e. g. ribocil and 5FDQD, have been shown to kill bacteria (Figure 1). 13,14 Riboflavin is known to bind to both the FMN riboswitch and riboflavin kinase.…”

The promise of endogenous and exogenous riboflavin in anti-infection

“…In the presence of FMN, they regulate the biosynthesis and transport of riboflavin in bacteria [ 34 , 35 ]. Importantly, they are specific to bacteria and absent in humans [ 36 ]. Here, several antibacterial agents, which include analogues of the riboflavin biosynthesis pathway, such as ribocil, roseoflavin (RoF), 8-demethyl-8-aminoriboflavin (AF), and 5-(3-(4-fluorophenyl)butyl)-7,8-dimethylpyrido[3,4-b]quinoxaline-1,3(2 H,5 H)-dione (5FDQD), protect against the pathogens by targeting the FMN riboswitch.…”