Targeting a microbiota Wolbachian aminoacyl-tRNA synthetase to block its pathogenic host

The interplay between humans and their microbiome is crucial for various physiological processes, including nutrient absorption, immune defense, and maintaining homeostasis. Microbiome alterations can directly contribute to diseases or heighten their likelihood. This relationship extends beyond huma...

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Bibliographic Details
Published in:Science advances 2024-07, Vol.10 (28), p.eado1453
Main Authors: Hoffmann, Guillaume, Lukarska, Maria, Clare, Rachel H, Masters, Ellen K G, Johnston, Kelly L, Ford, Louise, Turner, Joseph D, Ward, Steve A, Taylor, Mark J, Jensen, Malene Ringkjøbing, Palencia, Andrés
Format: Article
Language:English
Subjects:
Amino Acyl-tRNA Synthetases
Amino Acyl-tRNA Synthetases - antagonists & inhibitors
Amino Acyl-tRNA Synthetases - metabolism
Animals
Biomedicine and Life Sciences
Boron Compounds
Boron Compounds - chemistry
Boron Compounds - pharmacology
Crystallography, X-Ray
Humans
Leucine-tRNA Ligase
Leucine-tRNA Ligase - antagonists & inhibitors
Leucine-tRNA Ligase - metabolism
Life Sciences
Microbiology
Microbiota
Models, Molecular
SciAdv r-articles
Symbiosis
Wolbachia
Wolbachia - drug effects
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Summary:The interplay between humans and their microbiome is crucial for various physiological processes, including nutrient absorption, immune defense, and maintaining homeostasis. Microbiome alterations can directly contribute to diseases or heighten their likelihood. This relationship extends beyond humans; microbiota play vital roles in other organisms, including eukaryotic pathogens causing severe diseases. Notably, , a bacterial microbiota, is essential for parasitic worms responsible for lymphatic filariasis and onchocerciasis, devastating human illnesses. Given the lack of rapid cures for these infections and the limitations of current treatments, new drugs are imperative. Here, we disrupt 's symbiosis with pathogens using boron-based compounds targeting an unprecedented enzyme, leucyl-tRNA synthetase (LeuRS), effectively inhibiting its growth. Through a compound demonstrating anti- efficacy in infected cells, we use biophysical experiments and x-ray crystallography to elucidate the mechanism behind LeuRS inhibition. We reveal that these compounds form adenosine-based adducts inhibiting protein synthesis. Overall, our study underscores the potential of disrupting key microbiota to control infections.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.ado1453