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Mycobacteriology and Aerobic Actinomycetes

Characterization of Genomic Variants Associated with Resistance to Bedaquiline and Delamanid in Naive Mycobacterium tuberculosis Clinical Strains

S. Battaglia, A. Spitaleri, A. M. Cabibbe, C. J. Meehan, C. Utpatel, N. Ismail, S. Tahseen, A. Skrahina, N. Alikhanova, S. M. Mostofa Kamal, A. Barbova, S. Niemann, R. Groenheit, A. S. Dean, M. Zignol, L. Rigouts, D. M. Cirillo
Geoffrey A. Land, Editor
S. Battaglia
aEmerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
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A. Spitaleri
aEmerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
bCenter for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
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A. M. Cabibbe
aEmerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
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C. J. Meehan
cSchool of Chemistry and Biosciences, University of Bradford, Bradford, United Kingdom
dUnit of Mycobacteriology, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
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C. Utpatel
eMolecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Germany
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N. Ismail
fCentre for Tuberculosis, National Institute for Communicable Diseases, National Health Laboratory Services, Johannesburg, South Africa
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S. Tahseen
gNational TB Reference Laboratory, National Tuberculosis Control Program, Islamabad, Pakistan
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A. Skrahina
hRepublic Research and Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus
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N. Alikhanova
iScientific Research Institute of Lung Diseases, Ministry of Health, Baku, Azerbaijan
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S. M. Mostofa Kamal
jNational TB Reference Laboratory, National Institute of Diseases of the Chest and Hospital, Dhaka, Bangladesh
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A. Barbova
kCentral Reference Laboratory on Tuberculosis Microbiological Diagnostics, Ministry of Health, Kiev, Ukraine
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S. Niemann
eMolecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Germany
lGerman Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
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R. Groenheit
mUnit for Laboratory Surveillance of Bacterial Pathogens, Public Health Agency of Sweden, Solna, Sweden
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A. S. Dean
nGlobal TB Programme, World Health Organization, Geneva, Switzerland
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M. Zignol
nGlobal TB Programme, World Health Organization, Geneva, Switzerland
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L. Rigouts
dUnit of Mycobacteriology, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
oDepartment of Biomedical Sciences, Antwerp University, Antwerp, Belgium
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D. M. Cirillo
aEmerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Geoffrey A. Land
Carter BloodCare & Baylor University Medical Center
Roles: Editor
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DOI: 10.1128/JCM.01304-20
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ABSTRACT

The role of mutations in genes associated with phenotypic resistance to bedaquiline (BDQ) and delamanid (DLM) in Mycobacterium tuberculosis complex (MTBc) strains is poorly characterized. A clear understanding of the genetic variants’ role is crucial to guide the development of molecular-based drug susceptibility testing (DST). In this work, we analyzed all mutations in candidate genomic regions associated with BDQ- and DLM-resistant phenotypes using a whole-genome sequencing (WGS) data set from a collection of 4,795 MTBc clinical isolates from six countries with a high burden of tuberculosis (TB). From WGS analysis, we identified 61 and 163 unique mutations in genomic regions potentially involved in BDQ- and DLM-resistant phenotypes, respectively. Importantly, all strains were isolated from patients who likely have never been exposed to these medicines. To characterize the role of mutations, we calculated the free energy variation upon mutations in the available protein structures of Ddn (DLM), Fgd1 (DLM), and Rv0678 (BDQ) and performed MIC assays on a subset of MTBc strains carrying mutations to assess their phenotypic effect. The combination of structural and phenotypic data allowed for cataloguing the mutations clearly associated with resistance to BDQ (n = 4) and DLM (n = 35), only two of which were previously described, as well as about a hundred genetic variants without any correlation with resistance. Significantly, these results show that both BDQ and DLM resistance-related mutations are diverse and distributed across the entire region of each gene target, which is of critical importance for the development of comprehensive molecular diagnostic tools.

FOOTNOTES

    • Received 29 May 2020.
    • Returned for modification 22 June 2020.
    • Accepted 2 September 2020.
    • Accepted manuscript posted online 9 September 2020.
  • Supplemental material is available online only.

  • Copyright © 2020 American Society for Microbiology.

All Rights Reserved.

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Characterization of Genomic Variants Associated with Resistance to Bedaquiline and Delamanid in Naive Mycobacterium tuberculosis Clinical Strains
S. Battaglia, A. Spitaleri, A. M. Cabibbe, C. J. Meehan, C. Utpatel, N. Ismail, S. Tahseen, A. Skrahina, N. Alikhanova, S. M. Mostofa Kamal, A. Barbova, S. Niemann, R. Groenheit, A. S. Dean, M. Zignol, L. Rigouts, D. M. Cirillo
Journal of Clinical Microbiology Oct 2020, 58 (11) e01304-20; DOI: 10.1128/JCM.01304-20

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Characterization of Genomic Variants Associated with Resistance to Bedaquiline and Delamanid in Naive Mycobacterium tuberculosis Clinical Strains
S. Battaglia, A. Spitaleri, A. M. Cabibbe, C. J. Meehan, C. Utpatel, N. Ismail, S. Tahseen, A. Skrahina, N. Alikhanova, S. M. Mostofa Kamal, A. Barbova, S. Niemann, R. Groenheit, A. S. Dean, M. Zignol, L. Rigouts, D. M. Cirillo
Journal of Clinical Microbiology Oct 2020, 58 (11) e01304-20; DOI: 10.1128/JCM.01304-20
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KEYWORDS

bedaquiline
delamanid
Mycobacterium tuberculosis
resistance to new drugs
whole-genome sequencing

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