Characterization of ndh gene of isoniazid resistant and susceptible Mycobacterium tuberculosis isolates from Brazil

Cardoso, Rosilene Fressatti; Cardoso, Maria Helena; Leite, Clarice Queico Fujimura; Sato, Daisy Nakamura; Mamizuka, Elsa Masae; Hirata, Rosário Dominguez Crespo; Mello, Fernando F. de; Hirata, Mário Hiroyuki

doi:10.1590/s0074-02762007000100009

Cited by 32 publications

(14 citation statements)

References 17 publications

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“…In our study, we observed three mutations in this gene (V18A, A226E, and N316K codons). Mutations in V18A have been previously described in INH-susceptible and -resistant isolates (17), but the contribution of this mutation in the INH-resistant phenotype was unknown, whereas mutations in A226E and N316K have not been previously reported in M. tuberculosis or in Mycobacterium smegmatis. Therefore, the contribution of these mutations in INH and ETH resistance is uncertain.…”

Section: Cross-resistance To Inh and Eth In M Tuberculosis Clinical mentioning

confidence: 96%

“…The ndh gene encodes NADH dehydrogenase, which regulates the NADH/NAD ϩ ratio. Mutations in ndh would result in an increased intracellular NADH concentration, leading to the cross-resistance to both the drugs (16,17). Mutations in ethR, a negative transcriptional regulator of the expression of EthA, lead to ETH resistance (9, 18).…”

Section: Ethionamide (Eth) Is An Antibiotic Used For the Treatment Ofmentioning

confidence: 99%

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Genotypic Analysis of Genes Associated with Independent Resistance and Cross-Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis Clinical Isolates

Rueda

Realpe

Mejía

et al. 2015

Antimicrob Agents Chemother

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d Ethionamide (ETH) is an antibiotic used for the treatment of multidrug-resistant (MDR) tuberculosis (TB) (MDR-TB), and its use may be limited with the emergence of resistance in the Mycobacterium tuberculosis population. ETH resistance in M. tuberculosis is phenomenon independent or cross related when accompanied with isoniazid (INH) resistance. In most cases, resistance to INH and ETH is explained by mutations in the inhA promoter and in the following genes: katG, ethA, ethR, mshA, ndh, and inhA. We sequenced the above genes in 64 M. tuberculosis isolates (n ‫؍‬ 57 ETH-resistant MDR-TB isolates; n ‫؍‬ 3 ETH-susceptible MDR-TB isolates; and n ‫؍‬ 4 fully susceptible isolates). Each isolate was tested for susceptibility to first-and second-line drugs using the agar proportion method. Mutations were observed in ETH-resistant MDR-TB isolates at the following rates: 100% in katG, 72% in ethA, 45.6% in mshA, 8.7% in ndh, and 33.3% in inhA or its promoter. Of the three ETH-susceptible MDR-TB isolates, all showed mutations in katG; one had a mutation in ethA, and another, in mshA and inhA. Finally, of the four fully susceptible isolates, two showed no detectable mutation in the studied genes, and two had mutations in mshA gene unrelated to the resistance. Mutations not previously reported were found in the ethA, mshA, katG, and ndh genes. The concordance between the phenotypic susceptibility testing to INH and ETH and the sequencing was 1 and 0.45, respectively. Among isolates exhibiting INH resistance, the high frequency of independent resistance and cross-resistance with ETH in the M. tuberculosis isolates suggests the need to confirm the susceptibility to ETH before considering it in the treatment of patients with MDR-TB. E thionamide (ETH), a structural analog of isoniazid (INH), is a second-line drug used in the treatment of multidrug-resistant tuberculosis (MDR-TB) (1). Both ETH and INH are classified as prodrugs that are activated by different mycobacterial enzymes. INH is activated by the katG-encoded catalase-peroxidase, and ETH is activated by the ethA-encoded monooxygenase (2, 3). The activated INH and ETH drugs share the same molecular target, i.e., the NADH-dependent enoyl-acyl carrier protein reductase InhA, which is involved in the long-chain mycolic acid biosynthesis pathway (4). Therefore, the cross-resistance between INH and ETH can be detected in Mycobacterium tuberculosis clinical isolates in the case of mutations affecting the common target, which may occur when patients have previously been treated with INH and not with ETH (5). The frequency of cross-resistance differs between countries: 100% in Korea (6), 95.12% in Argentina (7), 94% in Brazil (8), 62% in France (9), and 13.8% in Thailand (10).Resistance to INH and ETH is mainly due to the chromosomal mutations. The mutation-carrying genes, such as those encoding the enzymes KatG (11,12) and EthA (13,14), are associated with individual resistance to INH and ETH, respectively. Mutations at the inhA promoter region or inhA gene result in the ove...

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Section: Cross-resistance To Inh and Eth In M Tuberculosis Clinical mentioning

confidence: 96%

Section: Ethionamide (Eth) Is An Antibiotic Used For the Treatment Ofmentioning

confidence: 99%

Genotypic Analysis of Genes Associated with Independent Resistance and Cross-Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis Clinical Isolates

Rueda

Realpe

Mejía

et al. 2015

Antimicrob Agents Chemother

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“…As the development of non-phenothiazine inhibitors of NDH2 progresses 140, 141 , attention must be paid to potential cross-resistance with isoniazid-resistant mutants that contain mutations in NDH2 (Ref. 142). …”

Section: Inhibiting Energy Metabolism In Tuberculosismentioning

confidence: 99%

Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections

et al. 2010

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Persistent infections involving slow-growing or non-growing bacteria are hard to treat with antibiotics that target biosynthetic processes in growing cells. Consequently, there is a need for antimicrobials that can treat infections containing dormant bacteria. In this Review, we discuss the emerging concept that disrupting the bacterial membrane bilayer or proteins that are integral to membrane function (including membrane potential and energy metabolism) in dormant bacteria is a strategy for treating persistent infections. The clinical applicability of these approaches is exemplified by the efficacy of lipoglycopeptides that damage bacterial membranes and of the diarylquinoline TMC207, which inhibits membrane-bound ATP synthase. Despite some drawbacks, membrane-active agents form an important new means of eradicating recalcitrant, non-growing bacteria.

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“…In humans INH is readily absorbed by the gastrointestinal tract and is metabolized by N-acetyltransferases (NAT 2) present in liver and gastrointestinal tract into isonicotinic acid (INA) and acetylhydrazine (AH) (19). Many laboratories have reported INH resistant MTB strains with no known mutations (20,21,22) suggesting possible existence of other strategies to survive in the presence of INH. This made us wonder if acetyltransferases in MTB, like NAT2 of liver and gastrointestinal tract, can also inactivate INH by acetylation.…”

Section: Discussionmentioning

confidence: 99%

Acetylation of isoniazid - a novel mechanism of isoniazid resistance inMycobacterium tuberculosis

Arun

Madhavan

Abraham

et al. 2020

Preprint

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Characterization of ndh gene of isoniazid resistant and susceptible Mycobacterium tuberculosis isolates from Brazil

Cited by 32 publications

References 17 publications

Genotypic Analysis of Genes Associated with Independent Resistance and Cross-Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis Clinical Isolates

Genotypic Analysis of Genes Associated with Independent Resistance and Cross-Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis Clinical Isolates

Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections

Acetylation of isoniazid - a novel mechanism of isoniazid resistance inMycobacterium tuberculosis

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