Trans-translation is essential in the human pathogen Legionella pneumophila

Brunel, Romain; Charpentier, Xavier

doi:10.1038/srep37935

Cited by 24 publications

(38 citation statements)

References 68 publications

(81 reference statements)

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“…Trans-translation is essential in species lacking alternative mechanisms (16). In agreement with these observations, alternative ribosome-rescue systems are absent in members of the Legionellaceae genus and we indeed found that trans-translation is essential for L. pneumophila growth and infection of its cellular host (32). In L. pneumophila, expressing the alternate rescue factor ArfA from E. coli can compensate for the loss of transtranslation activity indicating that the ribosome-dissociating activity of the trans-translation system is the sole function required for viability (32).…”

Section: Introductionsupporting

confidence: 89%

“…On L. pneumophila, several results led us to question the link between inhibition of transtranslation and antibiotic activity. First, no synergy was found between KKL-35 and ribosome-targeting antibiotics, whereas we previously found that a reduction in tmRNA levels led to an increased susceptibility of L. pneumophila to such antibiotics (32). Second, L. pneumophila cells treated with KKL-35 did not display the filamentation phenotype observed in cells lacking tmRNA.…”

Section: Discussionmentioning

confidence: 78%

“…Lack of trans-translation increases the sensitivity to ribosome-targeting antibiotics in E. coli (38,39) and in L. pneumophila (32). The L. pneumophila strains ssrA ind carrying an IPTG-inducible allele of the tmRNA-encoding gene ssrA is unable to grow if IPTG is not supplied in the medium (32). Low levels of IPTG allow growth with artificially reduced levels of tmRNA, resulting in increased susceptibility to erythromycin and chloramphenicol (32).…”

Section: Kkl-35 Does Not Induce Phenotypes Associated With Loss Of Trmentioning

confidence: 99%

“…The L. pneumophila strains ssrA ind carrying an IPTG-inducible allele of the tmRNA-encoding gene ssrA is unable to grow if IPTG is not supplied in the medium (32). Low levels of IPTG allow growth with artificially reduced levels of tmRNA, resulting in increased susceptibility to erythromycin and chloramphenicol (32). Complete lack of trans-translation may further increase the sensitivity of L. pneumophila to these antibiotics.…”

Section: Kkl-35 Does Not Induce Phenotypes Associated With Loss Of Trmentioning

confidence: 99%

“…L. pneumophila Paris was transformed with the plasmid pX5, a pMMB207C derivative harboring the gfp+ gene under a strong constitutive promoter and used for live monitoring of intracellular multiplication by fluorescence reading. The tmRNA mutant strains ssrA ind and ssrA ind /pArfA were previously described (32). ACES-Yeast Extract broth medium (AYE) was prepared with 10 g/L ACES (N-(2-acetamido)-2-aminoethanesulfonic acid), 12g/L yeast extract, 0.3 g/L iron III pyrophosphate and 0.5g/L L-cysteine.…”

Section: Strains Growth Media and Antibiotics Usedmentioning

confidence: 99%

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KKL-35 exhibits potent antibiotic activity againstLegionellaspecies independently of trans-translation inhibition

Brunel

Descours

Durieux

et al. 2017

Preprint

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trans-Translation is a ribosome-rescue system that is ubiquitous in bacteria. Small molecules defining a new family of oxadiazole compounds that inhibit trans-translation have been found to have broad-spectrum antibiotic activity. We sought to determine the activity of KKL-35, a potent member of the oxadiazole family, against the human pathogen Legionella pneumophila and other related species that can also cause Legionnaires' disease (LD). Consistent with the essential nature of trans-translation in L. pneumophila, KKL-35 inhibited the growth of all tested strains at submicromolar concentrations. KKL-35 was also active against other LD-causing Legionella species. KKL-35 remained equally active against L. pneumophila mutants that have evolved resistance to macrolides. KKL-35 inhibited the multiplication of L. pneumophila in human macrophages at several stages of infection. No resistant mutants could be obtained, even during extended and chronic exposure. Surprisingly, KKL-35 was not synergistic with other ribosome-targeting antibiotics and did not induce the filamentation phenotype observed in cells defective for trans-translation. Importantly, KKL-35 remained active against L. pneumophila mutants expressing an alternate ribosome-rescue system and lacking transfermessenger RNA, the essential component of trans-translation. These results indicate that the antibiotic activity of KKL-35 is not related to the specific inhibition of transtranslation and its mode of action remains to be identified. In conclusion, KKL-35 is an effective antibacterial agent against the intracellular pathogen L. pneumophila with no detectable resistance development. However, further studies are needed to better understand its mechanism of action and to assess further the potential of oxadiazoles in treatment. KEYWORDS Legionella, trans-translationL egionella pneumophila is a ubiquitous freshwater bacterium that infects a wide spectrum of environmental protozoans. Human-made systems, such as sanitary water networks and air-cooling towers, can disseminate contaminated water through aerosolization. The breathing of microscopic droplets contaminated with L. pneumophila can lead to infection of alveolar macrophages and development of a lifethreatening pneumonia called Legionnaires' disease (LD) or legionellosis. LD remains an important cause of both morbidity and mortality in Europe, with over 6,900 cases being reported in 2014 (1). Guidelines for the management of LD recommend the use of macrolides (with a preference for azithromycin) or fluoroquinolones (levofloxacin or moxifloxacin) to treat the infection (2, 3). Despite a rapid diagnosis and the correct administration of antibiotics, the death rate among those with LD is over 10% (4). L. Citation Brunel R, Descours G, Durieux I, Doublet P, Jarraud S, Charpentier X. 2018. KKL-35 exhibits potent antibiotic activity against Legionella species independently of transtranslation inhibition. Antimicrob Agents

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Section: Introductionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 78%

Section: Kkl-35 Does Not Induce Phenotypes Associated With Loss Of Trmentioning

confidence: 99%

Section: Kkl-35 Does Not Induce Phenotypes Associated With Loss Of Trmentioning

confidence: 99%

Section: Strains Growth Media and Antibiotics Usedmentioning

confidence: 99%

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KKL-35 exhibits potent antibiotic activity againstLegionellaspecies independently of trans-translation inhibition

Brunel

Descours

Durieux

et al. 2017

Preprint

Self Cite

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How hydrolytic exoribonucleases impact human disease: Two sides of the same story

et al. 2022

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RNAs are extremely important molecules inside the cell, which perform many different functions. For example, messenger RNAs, transfer RNAs and ribosomal RNAs are involved in protein synthesis, whereas noncoding RNAs have numerous regulatory roles. Ribonucleases (RNases) are the enzymes responsible for the processing and degradation of all types of RNAs, having multiple roles in every aspect of RNA metabolism. However, the involvement of RNases in disease is still not well understood. This review focuses on the involvement of the RNase II/RNB family of 3′–5′ exoribonucleases in human disease. This can be attributed to direct effects, whereby mutations in the eukaryotic enzymes of this family [defective in sister chromatid joining (Dis3; or Rrp44), Dis3‐like exonuclease 1 (Dis3L1; or Dis3L) and Dis3‐like exonuclease 2 (Dis3L2)] are associated with a disease, or indirect effects, whereby mutations in the prokaryotic counterparts of RNase II/RNB family (RNase II and/or RNase R) affect the physiology and virulence of several human pathogens. In this review, we compare the structural and biochemical characteristics of the members of the RNase II/RNB family of enzymes. The outcomes of mutations impacting enzymatic function are revisited, in terms of both the direct and indirect effects on disease. Furthermore, we also describe the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) viral exoribonuclease and its importance to combat the COVID‐19 pandemic. As a result, RNases may be a good therapeutic target to reduce bacterial and viral pathogenicity. These are the two perspectives on RNase II/RNB family enzymes that are presented in this review.

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An emerging field: Post‐translational modification in microbiome

2022

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Post‐translational modifications (PTMs) play an essential role in most biological processes. PTMs on human proteins have been extensively studied. Studies on bacterial PTMs are emerging, which demonstrate that bacterial PTMs are different from human PTMs in their types, mechanisms and functions. Few PTM studies have been done on the microbiome. Here, we reviewed several studied PTMs in bacteria including phosphorylation, acetylation, succinylation, glycosylation, and proteases. We discussed the enzymes responsible for each PTM and their functions. We also summarized the current methods used to study microbiome PTMs and the observations demonstrating the roles of PTM in the microbe‐microbe interactions within the microbiome and their interactions with the environment or host. Although new methods and tools for PTM studies are still needed, the existing technologies have made great progress enabling a deeper understanding of the functional regulation of the microbiome. Large‐scale application of these microbiome‐wide PTM studies will provide a better understanding of the microbiome and its roles in the development of human diseases.

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Trans-translation is essential in the human pathogen Legionella pneumophila

Cited by 24 publications

References 68 publications

KKL-35 exhibits potent antibiotic activity againstLegionellaspecies independently of trans-translation inhibition

KKL-35 exhibits potent antibiotic activity againstLegionellaspecies independently of trans-translation inhibition

How hydrolytic exoribonucleases impact human disease: Two sides of the same story

An emerging field: Post‐translational modification in microbiome

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