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. 2024 Jan 10;68(1):e0109623.
doi: 10.1128/aac.01096-23. Epub 2023 Dec 1.

Loss-of-function mutations in ndh do not confer delamanid, ethionamide, isoniazid, or pretomanid resistance in Mycobacterium tuberculosis

Sushil Pandey #  1 , Catherine Vilchèze #  2 , Jim Werngren #  3 , Arnold Bainomugisa  1 , Mikael Mansjö  3 , Ramona Groenheit  3 , Paolo Miotto  4 , Daniela M Cirillo  4 , Christopher Coulter  1 , Alain R Baulard  5 , Thomas Schön  6   7   8 , William R Jacobs Jr  2 , Kamel Djaout #  5 , Claudio U Köser #  9
Affiliations

Loss-of-function mutations in ndh do not confer delamanid, ethionamide, isoniazid, or pretomanid resistance in Mycobacterium tuberculosis

Sushil Pandey et al. Antimicrob Agents Chemother. .

Abstract

Results from clinical strains and knockouts of the H37Rv and CDC1551 laboratory strains demonstrated that ndh (Rv1854c) is not a resistance-conferring gene for isoniazid, ethionamide, delamanid, or pretomanid in Mycobacterium tuberculosis. This difference in the susceptibility to NAD-adduct-forming drugs compared with other mycobacteria may be driven by differences in the absolute intrabacterial NADH concentration.

Keywords: Mycobacterium tuberculosis; delamanid; ethionamide; isoniazid; pretomanid.

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Conflict of interest statement

D.M.C. is the co-chair of the Working Group of the Stop TB Partnership New Diagnostics and is an unpaid member of EUCAST subcommittee for antimicrobial susceptibility testing of mycobacteria, the CLSI mycobacterial committee, and the WHO Strategic and Technical Advisory Group for diagnostics. C.U.K. is a consultant for Becton Dickinson, the Foundation for Innovative New Diagnostics, the TB Alliance, and the WHO Global TB Programme. C.U.K.'s consulting for Becton Dickinson involves a collaboration with Janssen and Thermo Fisher Scientific. C.U.K. is collaborating with PZA Innovation and is an unpaid advisor to Cepheid and GenoScreen. C.U.K. worked as a consultant for the Stop TB Partnership and the WHO Regional Office for Europe. C.U.K. gave a paid educational talk for Oxford Immunotec. C.U.K. was an unpaid advisor to BioVersys.

Figures

Fig 1
Fig 1
Phylogenetic tree of Beijing (lineage 2) strains from Papua New Guinea provinces and associated DLM AST results (6). As shown by the purple triangle, the ndh frameshift mutation arose in 1992 (95% highest posterior density, 1985–1996) and is shared by most strains from the Daru-dominant clade A, whereas all strains from the National Capital District clade B lacked this mutation (grey tip labels correspond to Daru, red to National Capital District, and turquoise to other provinces, respectively). The first 14 columns depict different resistance mutations for first- and second-line drugs (with multiple colors where more than one mutation was involved). The last two columns show the distribution of the ndh frameshift (shown in purple), followed by the phenotypic DLM AST results for 14 strains, all of which tested susceptible, as indicated in green (Table S1). AG, aminoglycosides; AST, antimicrobial susceptibility testing; BDQ, bedaquiline; CAP, capreomycin; DLM, delamanid; E, ethambutol; ETH, ethionamide; FQ, fluoroquinolone; INH, isoniazid; R, rifampicin; p, promoter; PAS, para-aminosalicyclic acid; S, streptomycin; Z, pyrazinamide.
Fig 2
Fig 2
Correlation between intrabacterial NADH concentration and the sensitivity to INH (A) and ETH (B) for M. smegmatis, M. bovis BCG Pasteur, M. tuberculosis CDC1551, and their respective ndh mutants. Detailed references for source data can be found in Table S3 (1, 9).
See this image and copyright information in PMC

References

    1. Vilchèze C, Weisbrod TR, Chen B, Kremer L, Hazbón MH, Wang F, Alland D, Sacchettini JC, Jacobs Jr WR. 2005. Altered NADH/NAD+ ratio mediates coresistance to isoniazid and ethionamide in mycobacteria. Antimicrob Agents Chemother 49:708–720. doi:10.1128/AAC.49.2.708-720.2005 - DOI - PMC - PubMed
    1. Hayashi M, Nishiyama A, Kitamoto R, Tateishi Y, Osada-Oka M, Nishiuchi Y, Kaboso SA, Chen X, Fujiwara M, Inoue Y, Kawano Y, Kawasaki M, Abe T, Sato T, Kaneko K, Itoh K, Matsumoto S, Matsumoto M. 2020. Adduct formation of delamanid with NAD in mycobacteria. Antimicrob Agents Chemother 64:e01755-19. doi:10.1128/AAC.01755-19 - DOI - PMC - PubMed
    1. World Health Organization . 2022. WHO consolidated guidelines on tuberculosis. Module 4: treatment – drug-resistant tuberculosis treatment, 2022 update. https://apps.who.int/iris/handle/10665/365308. - PubMed
    1. Bainomugisa A, Lavu E, Hiashiri S, Majumdar S, Honjepari A, Moke R, Dakulala P, Hill-Cawthorne GA, Pandey S, Marais BJ, Coulter C, Coin L. 2018. Multi-clonal evolution of multi-drug-resistant/extensively drug-resistant Mycobacterium tuberculosis in a high-prevalence setting of Papua New Guinea for over three decades. Microb Genom 4:e000147. doi:10.1099/mgen.0.000147 - DOI - PMC - PubMed
    1. Gómez-González PJ, Perdigao J, Gomes P, Puyen ZM, Santos-Lazaro D, Napier G, Hibberd ML, Viveiros M, Portugal I, Campino S, Phelan JE, Clark TG. 2021. Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid. Sci Rep 11:19431. doi:10.1038/s41598-021-98862-4 - DOI - PMC - PubMed

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