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

Eduardo A. Troian, Heather M. Maldonado, Unnati Chauhan, Valdir C. Barth and Nancy A. Woychik ()
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Eduardo A. Troian: Rutgers University, Robert Wood Johnson Medical School
Heather M. Maldonado: Rutgers University, Robert Wood Johnson Medical School
Unnati Chauhan: Rutgers University, Robert Wood Johnson Medical School
Valdir C. Barth: Federal University of Health Sciences of Porto Alegre (UFCSPA), R. Sarmento Leite, 245 - Centro Histórico
Nancy A. Woychik: Rutgers University, Robert Wood Johnson Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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 tRNASerCGA by cleavage at only one site within its anticodon, leading to growth arrest. Concomitant tRNASerCGA 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.

Date: 2023
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DOI: 10.1038/s41467-023-38844-4

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