tRNAs as Antibiotic Targets

Chopra, Shaileja; Reader, John S.

doi:10.3390/ijms16010321

Cited by 32 publications

(22 citation statements)

References 199 publications

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“…Moreover, ARS substrate-based modification such as exploiting the structure of tRNA can be considered. Trana Discovery has developed a modern bioinformatics tool to conduct detailed analyses of tRNAs and employed a high-throughput screening system with a fluorescent probe mimicking the T-loop region to identify novel drugs that bind at the anticodon stem loop region of tRNAs to inhibit pathogen growth [147]. In addition, despite the structural homology, specific sequence differences between prokaryotic and eukaryotic ARSs can be used to design discriminating and specific ARS-targeted drugs.…”

Section: Developing Bacterial Ars Inhibitorsmentioning

confidence: 99%

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

Lee

Kim

2018

Biochemical Pharmacology

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Despite remarkable advances in medical science, infection-associated diseases remain among the leading causes of death worldwide. There is a great deal of interest and concern at the rate at which new pathogens are emerging and causing significant human health problems. Expanding our understanding of how cells regulate signaling networks to defend against invaders and retain cell homeostasis will reveal promising strategies against infection. It has taken scientists decades to appreciate that eukaryotic aminoacyl-tRNA synthetases (ARSs) play a role as global cell signaling mediators to regulate cell homeostasis, beyond their intrinsic function as protein synthesis enzymes. Recent discoveries revealed that ubiquitously expressed standby cytoplasmic ARSs sense and respond to danger signals and regulate immunity against infections, indicating their potential as therapeutic targets for infectious diseases. In this review, we discuss ARS-mediated anti-infectious signaling and the emerging role of ARSs in antimicrobial immunity. In contrast to their ability to defend against infection, host ARSs are inevitably co-opted by viruses for survival and propagation. We therefore provide a brief overview of the communication between viruses and the ARS system. Finally, we discuss encouraging new approaches to develop ARSs as therapeutics for infectious diseases.

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Section: Developing Bacterial Ars Inhibitorsmentioning

confidence: 99%

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

Lee

Kim

2018

Biochemical Pharmacology

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“…We recently showed that TM84 does not behave like other stable aminoacyl-adenylate analogues but, instead, employs a unique tRNA-dependent inhibition mechanism 23 24 . TM84 binds only weakly to the LeuRS-active site on its own and requires the presence of tRNA Leu to form a tight binding ternary inhibition complex 23 .…”

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confidence: 99%

Structural characterization of antibiotic self-immunity tRNA synthetase in plant tumour biocontrol agent

et al. 2016

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Antibiotic-producing microbes evolved self-resistance mechanisms to avoid suicide. The biocontrol Agrobacterium radiobacter K84 secretes the Trojan Horse antibiotic agrocin 84 that is selectively transported into the plant pathogen A. tumefaciens and processed into the toxin TM84. We previously showed that TM84 employs a unique tRNA-dependent mechanism to inhibit leucyl-tRNA synthetase (LeuRS), while the TM84-producer prevents self-poisoning by expressing a resistant LeuRS AgnB2. We now identify a mechanism by which the antibiotic-producing microbe resists its own toxin. Using a combination of structural, biochemical and biophysical approaches, we show that AgnB2 evolved structural changes so as to resist the antibiotic by eliminating the tRNA-dependence of TM84 binding. Mutagenesis of key resistance determinants results in mutants adopting an antibiotic-sensitive phenotype. This study illuminates the evolution of resistance in self-immunity genes and provides mechanistic insights into a fascinating tRNA-dependent antibiotic with applications for the development of anti-infectives and the prevention of biocontrol emasculation.

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“…Due to these modifications aminoglycoside losses, its ability to bind with the ribosome and hence could not modify the protein synthesis of bacteria. In addition to this, bacteria follows efflux mechanism and rRNA mutations [16].…”

Section: Aminoglycoside Resistancementioning

confidence: 99%

Application of Nanostructures in Antimicrobial Therapy

et al. 2018

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There are many infectious diseases that may be biofilm mediated, medical device-mediated or from some other agent, are now becoming life-threatening. Despite of availability of many antimicrobial agents, new drugs or therapeutics, these infections have continued to be a global health challenge. Nowadays, conventional antimicrobial agents have failed against many infections due to the emergence of multiple drug-resistant strains. Even, if there is a therapeutic efficacy of these drugs, there inappropriate amounts are resulting in an adequate therapeutic index, local and systematic side effects, including irritation, reduction in gut flora and other manifestations. To overcome such situations, nanostructures have exclusive physicochemical properties as they are ultra small, their size can be controlled, greater surface area to mass ratio, high reactivity and functionalizable structure. Encapsulation of antimicrobial drugs in these nanoparticle systems helps in reducing many side effects. It also helps in the sustained release of drug for a larger time period. Several metal and metal oxide nanoparticles such as silver, gold, zinc, etc. have shown a promising antimicrobial activity. Liposomes, polymeric nanoparticles, dendrimers, and solid lipid nanoparticles have achieved great success as efficient antimicrobial drug delivery systems. These nanoparticles use multiple biological pathways to exert their antimicrobial mechanism such as cell wall disruption, inhibition of RNA synthesis, protein synthesis, etc. Moreover,these preparations of nanoparticles are more cost-effective than that of antibiotic synthesis with lesser or no side effects.

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tRNAs as Antibiotic Targets

Cited by 32 publications

References 199 publications

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

Structural characterization of antibiotic self-immunity tRNA synthetase in plant tumour biocontrol agent

Application of Nanostructures in Antimicrobial Therapy

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