KKL-35 exhibits potent antibiotic activity against Legionella species independently of trans-translation inhibition
Autor: | Sophie Jarraud, Patricia Doublet, Isabelle Durieux, Xavier Charpentier, Ghislaine Descours, Romain Brunel |
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Přispěvatelé: | Transfert de gène horizontal chez les bactéries pathogènes – Horizontal gene transfer in bacterial pathogens, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathogenèse des légionelles- Legionella pathogenesis (LegioPath), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS) |
Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0303 health sciences
biology 030306 microbiology medicine.drug_class Antibiotics Legionella Human pathogen biology.organism_classification Legionella pneumophila Virology [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology 3. Good health Microbiology trans-translation 03 medical and health sciences Mechanism of action [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology medicine [SDV.IMM]Life Sciences [q-bio]/Immunology medicine.symptom Mode of action Bacteria Trans-translation 030304 developmental biology Antibacterial agent |
Zdroj: | Antimicrobial Agents and Chemotherapy Antimicrobial Agents and Chemotherapy, 2018, 62 (2), ⟨10.1128/AAC.01459-17⟩ Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2018, 62 (2), ⟨10.1128/AAC.01459-17⟩ |
ISSN: | 0066-4804 1098-6596 |
DOI: | 10.1101/135798 |
Popis: | 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 pathogenLegionella pneumophilaand other related species that can also cause Legionnaires disease (LD). Consistent with the essential nature of trans-translation inL. pneumophila, KKL-35 inhibits growth of all tested strains at sub-micromolar concentrations. KKL-35 is also active against other LD-causingLegionellaspecies. KKL-35 remains equally active againstL. pneumophilamutants that have evolved resistance to macrolides. KKL-35 inhibits multiplication ofL. pneumophilain human macrophages at several stages of infection. No resistant mutants could be obtained, even during extended and chronic exposure. Surprisingly, KKL-35 is not synergistic with other ribosome-targeting antibiotics and does not induce the filamentation phenotype observed in cells defective for trans-translation. Importantly, KKL-35 remains active againstL. pneumophilamutants expressing an alternate ribosome-rescue system and lacking tmRNA, the essential component of trans-translation. These results indicate that the antibiotic activity of KKL-35 is not related to the specific inhibition of trans-translation and its mode of action remains to be identified. In conclusion, KKL-35 is an effective antibacterial agent against the intracellular pathogenL. pneumophilaand with no detectable resistance. However, further studies are needed to better understand its mechanism of action and to assess further the potential of oxadiazoles in treatment. |
Databáze: | OpenAIRE |
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