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Editor's Pick Mechanisms of Resistance

Rapidly Correcting Frameshift Mutations in the Mycobacterium tuberculosis orn Gene Produce Reversible Ethambutol Resistance and Small-Colony-Variant Morphology

Hassan Safi, Subramanya Lingaraju, Shuyi Ma, Seema Husain, Mainul Hoque, Patricia Soteropoulos, Tige Rustad, David R. Sherman, David Alland
Hassan Safi
aCenter for Emerging Pathogens, Department of Medicine, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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Subramanya Lingaraju
aCenter for Emerging Pathogens, Department of Medicine, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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Shuyi Ma
bCenter for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington, USA
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  • ORCID record for Shuyi Ma
Seema Husain
cGenomics Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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Mainul Hoque
cGenomics Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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Patricia Soteropoulos
cGenomics Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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Tige Rustad
bCenter for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington, USA
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David R. Sherman
dDepartment of Microbiology, University of Washington School of Medicine, Seattle, Washington, USA
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David Alland
aCenter for Emerging Pathogens, Department of Medicine, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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DOI: 10.1128/AAC.00213-20
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ABSTRACT

We have identified a previously unknown mechanism of reversible high-level ethambutol (EMB) resistance in Mycobacterium tuberculosis that is caused by a reversible frameshift mutation in the M. tuberculosis orn gene. A frameshift mutation in orn produces the small-colony-variant (SCV) phenotype, but this mutation does not change the MICs of any drug for wild-type M. tuberculosis. However, the same orn mutation in a low-level EMB-resistant double embB-aftA mutant (MIC = 8 μg/ml) produces an SCV with an EMB MIC of 32 μg/ml. Reversible resistance is indistinguishable from a drug-persistent phenotype, because further culture of these orn-embB-aftA SCV mutants results in rapid reversion of the orn frameshifts, reestablishing the correct orn open reading frame, returning the culture to normal colony size, and reversing the EMB MIC back to that (8 μg/ml) of the parental strain. Transcriptomic analysis of orn-embB-aftA mutants compared to wild-type M. tuberculosis identified a 27-fold relative increase in the expression of embC, which is a cellular target for EMB. Expression of embC in orn-embB-aftA mutants was also increased 5-fold compared to that in the parental embB-aftA mutant, whereas large-colony orn frameshift revertants of the orn-embB-aftA mutant had levels of embC expression similar to that of the parental embB-aftA strain. Reversible frameshift mutants may contribute to a reversible form of microbiological drug resistance in human tuberculosis.

FOOTNOTES

    • Received 3 February 2020.
    • Returned for modification 9 March 2020.
    • Accepted 18 June 2020.
    • Accepted manuscript posted online 22 June 2020.
  • Supplemental material is available online only.

  • Copyright © 2020 American Society for Microbiology.

All Rights Reserved.

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Rapidly Correcting Frameshift Mutations in the Mycobacterium tuberculosis orn Gene Produce Reversible Ethambutol Resistance and Small-Colony-Variant Morphology
Hassan Safi, Subramanya Lingaraju, Shuyi Ma, Seema Husain, Mainul Hoque, Patricia Soteropoulos, Tige Rustad, David R. Sherman, David Alland
Antimicrobial Agents and Chemotherapy Aug 2020, 64 (9) e00213-20; DOI: 10.1128/AAC.00213-20

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Rapidly Correcting Frameshift Mutations in the Mycobacterium tuberculosis orn Gene Produce Reversible Ethambutol Resistance and Small-Colony-Variant Morphology
Hassan Safi, Subramanya Lingaraju, Shuyi Ma, Seema Husain, Mainul Hoque, Patricia Soteropoulos, Tige Rustad, David R. Sherman, David Alland
Antimicrobial Agents and Chemotherapy Aug 2020, 64 (9) e00213-20; DOI: 10.1128/AAC.00213-20
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KEYWORDS

cas genes
drug resistance
embC
ethambutol
orn
reversible frameshift
small-colony variant

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