(Non-)translational medicine: targeting bacterial RNA (original) (raw)
Related papers
RNA as A Potent Target for Antibacterial Drug Discovery
Biomedical Journal of Scientific & Technical Research
The development of novel antibiotics is becoming a real emergency due to the growing number of multidrug-resistant pathogenic bacteria. This is also a global problem due to mass production and application of various antibiotics both in human and veterinary medicine. Therefore, we need not only to create novel antibiotics but also to speed up the development pipeline. This may be achieved by using novel targets for antibacterial drug discovery. In this review, we focus our attention on several different types of RNA molecules that have been used as antibacterial drug targets. The RNA is the most ambiguous biopolymer in the cell, which carries many different functions. For instance, tRNAs, rRNAs, and mRNAs are essential for gene expression both in the pro-and eukaryotes. However, all these types of RNAs have sequences and something 3D structures that are specific for bacteria only and can be used to shut down essential biochemical processes in bacteria only. All these features make RNA very potent target for antibacterial drug development.
Frontiers in Microbiology, 2017
The emergence of antibiotic resistance mechanisms among bacterial pathogens increases the demand for novel treatment strategies. Lately, the contribution of noncoding RNAs to antibiotic resistance and their potential value as drug targets became evident. RNA attenuator elements in mRNA leader regions couple expression of resistance genes to the presence of the cognate antibiotic. Trans-encoded small RNAs (sRNAs) modulate antibiotic tolerance by base-pairing with mRNAs encoding functions important for resistance such as metabolic enzymes, drug efflux pumps, or transport proteins. Bacteria respond with extensive changes of their sRNA repertoire to antibiotics. Each antibiotic generates a unique sRNA profile possibly causing downstream effects that may help to overcome the antibiotic challenge. In consequence, regulatory RNAs including sRNAs and their protein interaction partners such as Hfq may prove useful as targets for antimicrobial chemotherapy. Indeed, several compounds have been developed that kill bacteria by mimicking ligands for riboswitches controlling essential genes, demonstrating that regulatory RNA elements are druggable targets. Drugs acting on sRNAs are considered for combined therapies to treat infections. In this review, we address how regulatory RNAs respond to and establish resistance to antibiotics in bacteria. Approaches to target RNAs involved in intrinsic antibiotic resistance or virulence for chemotherapy will be discussed.
RNA decay: a novel therapeutic target in bacteria
Wiley Interdisciplinary Reviews: RNA, 2012
The need for novel antibiotics is greater now than perhaps any time since the pre-antibiotic era. Indeed, the recent collapse of most pharmaceutical antibacterial groups, combined with the emergence of hypervirulent and pan-antibiotic-resistant bacteria have, in effect, created a "perfect storm" that has severely compromised infection treatment options and led to dramatic increases in the incidence and severity of bacterial infections. Simply put, it is imperative that we develop new classes of antibiotics for the therapeutic intervention of bacterial infections. In that regard, RNA degradation is an essential biological process that has not been exploited for antibiotic development. Herein we discuss the factors that govern bacterial RNA degradation, highlight members of this machinery that represent attractive antimicrobial drug development targets and describe the use of high-throughput screening as a means of developing antimicrobials that target these enzymes. Such agents would represent first-in-class antibiotics that would be less apt to inactivation by currently encountered enzymatic antibiotic-resistance determinants.
Insights Into Non-coding RNAs as Novel Antimicrobial Drugs
Frontiers in Genetics
Multidrug resistant bacteria are a serious worldwide problem, especially carbapenemresistant Enterobacteriaceae (such as Klebsiella pneumoniae and Escherichia coli), Acinetobacter baumannii and Pseudomonas aeruginosa. Since the emergence of extensive and pan-drug resistant bacteria there are few antibiotics left to treat patients, thus novel RNA-based strategies are being considered. Here, we examine the current situation of different non-coding RNAs found in bacteria as well as their function and potential application as antimicrobial agents. Furthermore, we discuss the factors that may contribute in the efficient development of RNA-based drugs, the limitations for their implementation and the use of nanocarriers for delivery.
Developing New Tools to Fight Human Pathogens: A Journey through the Advances in RNA Technologies
Microorganisms
A long scientific journey has led to prominent technological advances in the RNA field, and several new types of molecules have been discovered, from non-coding RNAs (ncRNAs) to riboswitches, small interfering RNAs (siRNAs) and CRISPR systems. Such findings, together with the recognition of the advantages of RNA in terms of its functional performance, have attracted the attention of synthetic biologists to create potent RNA-based tools for biotechnological and medical applications. In this review, we have gathered the knowledge on the connection between RNA metabolism and pathogenesis in Gram-positive and Gram-negative bacteria. We further discuss how RNA techniques have contributed to the building of this knowledge and the development of new tools in synthetic biology for the diagnosis and treatment of diseases caused by pathogenic microorganisms. Infectious diseases are still a world-leading cause of death and morbidity, and RNA-based therapeutics have arisen as an alternative way...
Why Some Riboswitches are Suitable Targets forAntibacterial Drug Discovery
2020
The global spread of a growing number of antibiotic-resistant strains of human pathogenic bacteria imposes the pressing need for the development of novel antibiotics using novel antibacterial drugs. One promising strategy is to use novel targets for antibacterial drug discovery such as bacterial riboswitches. They have conservative and well-known RNA sequences and structures and regulate the synthesis of essential metabolites in different pathogenic bacteria by sensing their presence in the cell. In this review, we summarized three different bioinformatic-based criteria for the assessment of the suitability of riboswitches as suitable drug targets. They enable us to focus our research on the most suitable and promising riboswitches as antibacterial drug targets.
Journal of Pharmacy and Pharmacology, 2002
During the last few years, antibiotic multiresistance has been increasing, not only in hospitals, but also, more worryingly, in general medicine. Different ways are being explored to bypass this problem. RNA-acting antibiotics such as aminosides (aminoglycosides) bind to bacterial RNA causing premature termination of proteins and mistranslation in bacteria. It is now possible to study the interactions of such antibiotics with their target by in-vitro selection of RNA molecules that recognize these antibiotics (RNA aptamers, SELEX method). The knowledge of the antibiotic-RNA interactions represents a promising way for the rational design of new bioactive compounds less susceptible to bacterial resistance.
Antibiotics
Antibiotic resistance (AR) is an acute problem that results in prolonged and debilitating illnesses. AR mortality worldwide is growing and causes a pressing need to research novel mechanisms of action and untested target molecules. This article presents in silico analyses of eight bacterial riboswitches for their suitability for antibacterial drug targets. Most bacterial riboswitches are located in the 5′-untranslated region of messenger RNAs, act as allosteric cis-acting gene control elements, and have not been found in humans before. Sensing metabolites, the riboswitches regulate the synthesis of vital cellular metabolites in various pathogenic bacteria. The analyses performed in this article represent a complete and informative genome-wide bioinformatics analysis of the adequacy of eight riboswitches as antibacterial drug targets in different pathogenic bacteria based on four criteria. Due to the ability of the riboswitch to control biosynthetic pathways and transport proteins of...
The bacterial ribosome as a target for antibiotics
Nature Reviews Microbiology, 2005
Many clinically useful antibiotics exert their antimicrobial effects by blocking protein synthesis on the bacterial ribosome. The structure of the ribosome has recently been determined by X-ray crystallography, revealing the molecular details of the antibiotic-binding sites. The crystal data explain many earlier biochemical and genetic observations, including how drugs exercise their inhibitory effects, how some drugs in combination enhance or impede each other's binding, and how alterations to ribosomal components confer resistance. The crystal structures also provide insight as to how existing drugs might be derivatized (or novel drugs created) to improve binding and circumvent resistance.
Potential and use of bacterial small RNAs to combat drug resistance: a systematic review
Infection and drug resistance, 2017
Over the decades, new antibacterial agents have been developed in an attempt to combat drug resistance, but they remain unsuccessful. Recently, a novel class of bacterial gene expression regulators, bacterial small RNAs (sRNAs), has received increasing attention toward their involvement in antibiotic resistance. This systematic review aimed to discuss the potential of these small molecules as antibacterial drug targets. Two investigators performed a comprehensive search of MEDLINE, EmBase, and ISI Web of Knowledge from inception to October 2016, without restriction on language. We included all in vitro and in vivo studies investigating the role of bacterial sRNA in antibiotic resistance. Risk of bias of the included studies was assessed by a modified guideline of Systematic Review Center for Laboratory Animal Experimentation (SYRCLE). Initial search yielded 432 articles. After exclusion of non-original articles, 20 were included in this review. Of these, all studies examined bacteri...