Deacylated tRNA Accumulation Is a Trigger for Bacterial Antibiotic Persistence Independent of the Stringent Response

Wood, Whitney N.; Mohler, Kyle; Rinehart, Jesse; Ibba, Michael

doi:10.1128/mbio.01132-21

Cited by 9 publications

(15 citation statements)

References 59 publications

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“…18 Biogenesis of the bacterial ribosome starts when the primary rRNAs are transcribed, including 23S, 16S, and 5S rRNA precursors and some transfer RNAs (tRNAs). 19 This process requires the participation of RNA polymerase (RNAP), a multi-subunit enzyme that synthesizes all types of RNA and catalyzes the transcription process of rDNA. 20 Precursors of rRNAs and tRNAs fold into a unique structure, then excised from their primary transcripts.…”

Section: Ribosomes and Ribosome Biogenesis Eukaryotic Ribosomementioning

confidence: 99%

“…115 For the 30S subunit, antibiotics prevent protein synthesis by inhibiting the formation of the ribosomal initiation complex, interfering with tRNA binding, and interfering with tRNA site transfer during translation. 19,116 Antibiotics targeting tRNA. Tetracycline is a broad-spectrum antibiotic that blocks bacterial protein synthesis.…”

Section: Mechanism Of Ribosome-targeting Antibioticsmentioning

confidence: 99%

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Ribosome biogenesis in disease: new players and therapeutic targets

Jiao

Liu

et al. 2023

Sig Transduct Target Ther

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The ribosome is a multi-unit complex that translates mRNA into protein. Ribosome biogenesis is the process that generates ribosomes and plays an essential role in cell proliferation, differentiation, apoptosis, development, and transformation. The mTORC1, Myc, and noncoding RNA signaling pathways are the primary mediators that work jointly with RNA polymerases and ribosome proteins to control ribosome biogenesis and protein synthesis. Activation of mTORC1 is required for normal fetal growth and development and tissue regeneration after birth. Myc is implicated in cancer development by enhancing RNA Pol II activity, leading to uncontrolled cancer cell growth. The deregulation of noncoding RNAs such as microRNAs, long noncoding RNAs, and circular RNAs is involved in developing blood, neurodegenerative diseases, and atherosclerosis. We review the similarities and differences between eukaryotic and bacterial ribosomes and the molecular mechanism of ribosome-targeting antibiotics and bacterial resistance. We also review the most recent findings of ribosome dysfunction in COVID-19 and other conditions and discuss the consequences of ribosome frameshifting, ribosome-stalling, and ribosome-collision. We summarize the role of ribosome biogenesis in the development of various diseases. Furthermore, we review the current clinical trials, prospective vaccines for COVID-19, and therapies targeting ribosome biogenesis in cancer, cardiovascular disease, aging, and neurodegenerative disease.

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Section: Ribosomes and Ribosome Biogenesis Eukaryotic Ribosomementioning

confidence: 99%

Section: Mechanism Of Ribosome-targeting Antibioticsmentioning

confidence: 99%

Ribosome biogenesis in disease: new players and therapeutic targets

Jiao

Liu

et al. 2023

Sig Transduct Target Ther

View full text Add to dashboard Cite

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“…Moreover, no effect of hibernation factors Rmf/Hpf is observed, suggesting different persistence mechanisms than ribosome dormancy formation in growing cells. Recent studies also show the existence of mechanisms triggering persistence independently of ppGpp or hibernation factors in bacteria ( Hossain et al., 2021 ; Wood et al., 2021 ). We show here that RaiA is one player enhancing persister formation in the Gram-negative bacterium V. cholerae.…”

Section: Discussionmentioning

confidence: 99%

Sleeping ribosomes: Bacterial signaling triggers RaiA mediated persistence to aminoglycosides

et al. 2021

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Summary Indole is a molecule proposed to be involved in bacterial signaling. We find that indole secretion is induced by sublethal tobramycin concentrations and increases persistence to aminoglycosides in V. cholerae . Indole transcriptomics showed increased expression of raiA , a ribosome associated factor. Deletion of raiA abolishes the appearance of indole dependent persisters to aminoglycosides, although its overexpression leads to 100-fold increase of persisters, and a reduction in lag phase, evocative of increased active 70S ribosome content, confirmed by sucrose gradient analysis. We propose that, under stress conditions, RaiA-bound inactive 70S ribosomes are stored as “sleeping ribosomes”, and are rapidly reactivated upon stress relief. Our results point to an active process of persister formation through ribosome protection during translational stress (e.g., aminoglycoside treatment) and reactivation upon antibiotic removal. Translation is a universal process, and these results could help elucidate a mechanism of persistence formation in a controlled, thus inducible way.

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“…The two-metal-ion mechanism is conserved in the MazG family across bacteria to phages (Mota et al, 2016;Huang et al, 2021;Wood et al, 2021). In the MazG (1-185) structure, one magnesium ion was present per subunit.…”

Section: The Magnesium-binding Sites and Enzymatic Activitymentioning

confidence: 99%

Structural analysis of the housecleaning nucleoside triphosphate pyrophosphohydrolase MazG from Mycobacterium tuberculosis

et al. 2023

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The housecleaning enzyme of Mycobacterium tuberculosis (Mtb), MazG, is a nucleoside triphosphate pyrophosphohydrolase (NTP-PPase) and can hydrolyze all canonical or non-canonical NTPs into NMPs and pyrophosphate. The Mycobacterium tuberculosis MazG (Mtb-MazG) contributes to antibiotic resistance in response to oxidative or nitrosative stress under dormancy, making it a promising target for treating TB in latent infection patients. However, the structural basis of Mtb-MazG is not clear. Here we describe the crystal structure of Mtb-MazG (1–185) at 2.7 Å resolution, composed of two similar folded spherical domains in tandem. Unlike other all-α NTP pyrophosphatases, Mtb-MazG has an N-terminal extra region composed of three α-helices and five β-strands. The second domain is global, with five α-helices located in the N-terminal domain. Gel-filtration assay and SAXS analysis show that Mtb-MazG forms an enzyme-active dimer in solution. In addition, the metal ion Mg2+ is bound with four negative-charged residues Glu119, Glu122, Glu138, and Asp141. Different truncations and site-directed mutagenesis revealed that the full-length dimeric form and the metal ion Mg2+ are indispensable for the catalytic activity of Mtb-MazG. Thus, our work provides new insights into understanding the molecular basis of Mtb-MazG.

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Deacylated tRNA Accumulation Is a Trigger for Bacterial Antibiotic Persistence Independent of the Stringent Response

Abstract: Bacterial antibiotic persistence is a transient physiological state wherein cells become dormant and thereby evade being killed by antibiotics. Once the antibiotic is removed, bacterial persisters are able to resuscitate and repopulate.

Cited by 9 publications

References 59 publications

Ribosome biogenesis in disease: new players and therapeutic targets

Ribosome biogenesis in disease: new players and therapeutic targets

Sleeping ribosomes: Bacterial signaling triggers RaiA mediated persistence to aminoglycosides

Structural analysis of the housecleaning nucleoside triphosphate pyrophosphohydrolase MazG from Mycobacterium tuberculosis

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