Abstract
Abstract Objectives The development of novel antibiotic compounds requires riboswitches; in fact, riboswitches are RNA elements present in the 5′ untranslated region of bacterial mRNA and have a metabolite-binding aptamer domain and an expression platform regulating the expression of vital genes. In the present research, one riboswitch, namely thi-box riboswitch with distinct regulatory mechanisms, was studied. It recognizes Thiamine Pyrophosphates (TPP) regulating TPP-biosynthesis genes in Escherichia coli. Methods First, the compounds similar to riboswitch ligands were studied, and their binding with the riboswitch and nucleosides was investigated by molecular docking. Then, compounds containing high binding energy were chosen, and their minimum inhibitory concentration in E. coli was determined by the MIC test. Finally, the binding of compounds to nucleotides and RNA was investigated by measuring the absorbance spectrum through NanoDrop and circular dichroism (CD). Results In the thi-box riboswitch, nalidixic acid was found to have the best binding energy (−5.31 kJ/mol), and it inhibited E. coli growth at the minimum inhibitory concentration of 125 μg/mL, and it could bind to ribonucleosides and RNA in vitro. Conclusions One possible mechanism involved in the action of nalidixic acid in inhibiting the E. coli growth is to influence thi-box riboswitch.
Highlights
In the past decade, the problem of multiple drug resistance (MDR) has increased relatively due to the extreme use of antibiotics
The crystal structure of the Thiamine Pyrophosphates (TPP) riboswitch was obtained from the Protein Data Bank (PDB ID 2HOJ)
The present study was aimed to investigate the potential of TPP riboswitches as a target for an antibacterial agent
Summary
The problem of multiple drug resistance (MDR) has increased relatively due to the extreme use of antibiotics. MDR is caused as a result of drug design, mostly relying on the restricted chemical frameworks providing the opportunity for pathogens to hook up the action mechanisms of antibiotics [1]. Riboswitches could be the generation of RNA-based targets. As RNA elements, they form and regulate receptors for individual small molecules and gene expression in response to ligand binding, respectively [2]. Riboswitches have two structural domains, one of which is an aptamer domain binding to a specific metabolite. Another domain is responsible for regulating gene expression. When a ligand binds to an aptamer domain, expression platform can bring about either transcription termination by formation a terminator hairpin or translation inhibition by sequestering the ribosome binding site [3]
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