Mycobacterium abscessus VapC5 toxin potentiates evasion of antibiotic killing by ribosome overproduction and activation of multiple resistance pathways

Mycobacterium abscessus (Mab) infections are inexplicably intractable to clearing after aggressive and lengthy treatment regimens. Here we discovered that acquisition of a single toxin-antitoxin system enables Mab to activate a phenotypic switch that enhances survival upon treatment with current fir...

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Bibliographic Details
Published in:	Nature communications Vol. 14; no. 1; p. 3705
Main Authors:	Troian, Eduardo A., Maldonado, Heather M., Chauhan, Unnati, Barth, Valdir C., Woychik, Nancy A.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 22-06-2023 Nature Publishing Group Nature Portfolio
Subjects:	45 45/88 45/91 631/326/22/1434 631/326/421 631/337/2019 631/337/475 631/337/574/1789 Amikacin Anti-Bacterial Agents - metabolism Anti-Bacterial Agents - pharmacology Anti-Infective Agents - metabolism Antibiotics Antimicrobial agents Antitoxins Cefoxitin Cell walls Depletion Humanities and Social Sciences Infections multidisciplinary Mycobacterium abscessus Mycobacterium abscessus - genetics Phenotypes Protein synthesis Proteins Ribosomes Ribosomes - metabolism RNA, Transfer - metabolism Science Science (multidisciplinary) Survival Toxins Toxins, Biological - metabolism Transcriptomes
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Summary:	Mycobacterium abscessus (Mab) infections are inexplicably intractable to clearing after aggressive and lengthy treatment regimens. Here we discovered that acquisition of a single toxin-antitoxin system enables Mab to activate a phenotypic switch that enhances survival upon treatment with current first-line antibiotics. This switch is tripped when the VapC5 toxin inactivates tRNA SerCGA by cleavage at only one site within its anticodon, leading to growth arrest. Concomitant tRNA SerCGA depletion then reprograms the transcriptome to favor synthesis of proteins naturally low in the cognate Ser UCG codon including the transcription factor WhiB7 and members of its regulon as well as the ribosomal protein family. This programmed stockpiling of ribosomes is predicted to override the efficacy of ribosome-targeting antibiotics while the growth arrest phenotype attenuates antibiotics targeting cell wall synthesis. In agreement, VapC5 increases Mab persister formation upon exposure to amikacin and the next-generation oxazolidinone tedizolid (both target ribosomes) or cefoxitin (inhibits cell wall synthesis). These findings expand the repertoire of genetic adaptations harnessed by Mab to survive assaults intended to eradicate it, as well as provide a much-needed framework for selection of shorter and more efficacious alternate treatment options for Mab infections using currently available antimicrobials whose targets are not confounded by VapC5. Mycobacterium abscessus (Mab) infections are difficult to clear with antibiotics. Here the authors show that clinical Mab strains can acquire a toxin-antitoxin system that enhances survival upon treatment with current first-line antibiotics through depletion of tRNA SerCGA and subsequent ribosome overproduction.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-023-38844-4