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Comparative analysis of mycobacterial NADH pyrophosphatase isoforms reveals a novel mechanism for isoniazid and ethionamide inactivation.

ABSTRACT: NADH pyrophosphatase (NudC) catalyses the hydrolysis of NAD(H) to AMP and NMN(H) [nicotinamide mononucleotide (reduced form)]. NudC multiple sequence alignment reveals that homologues from most Mycobacterium tuberculosis isolates, but not other mycobacterial species, have a polymorphism at the highly conserved residue 237. To elucidate the functional significance of this polymorphism, comparative analyses were performed using representative NudC isoforms from M. tuberculosis H37Rv (NudC(Rv)) and M. bovis BCG (NudC(BCG)). Biochemical analysis showed that the P237Q polymorphism prevents dimer formation, and results in a loss of enzymatic activity. Importantly, NudC(BCG) was found to degrade the active forms of isoniazid (INH), INH-NAD and ethionamide (ETH), ETH-NAD. Consequently, overexpression of NudC(BCG) in Mycobacterium smegmatis mc(2)155 and M. bovis BCG resulted in a high level of resistance to both INH and ETH. Further genetic studies showed that deletion of the nudC gene in M. smegmatis mc(2)155 and M. bovis BCG resulted in increased susceptibility to INH and ETH. Moreover, inactivation of NudC in both strains caused a defect in drug tolerance phenotype for both drugs in exposure assays. Taken together, these data suggest that mycobacterial NudC plays an important role in the inactivation of INH and ETH.

SUBMITTER: Wang XD

PROVIDER: S-EPMC3283747 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Comparative analysis of mycobacterial NADH pyrophosphatase isoforms reveals a novel mechanism for isoniazid and ethionamide inactivation.

Wang Xu-De XD Gu Jing J Wang Ting T Bi Li-Jun LJ Zhang Zhi-Ping ZP Cui Zong-Qiang ZQ Wei Hong-Ping HP Deng Jiao-Yu JY Zhang Xian-En XE

Molecular microbiology 20111103 6

NADH pyrophosphatase (NudC) catalyses the hydrolysis of NAD(H) to AMP and NMN(H) [nicotinamide mononucleotide (reduced form)]. NudC multiple sequence alignment reveals that homologues from most Mycobacterium tuberculosis isolates, but not other mycobacterial species, have a polymorphism at the highly conserved residue 237. To elucidate the functional significance of this polymorphism, comparative analyses were performed using representative NudC isoforms from M. tuberculosis H37Rv (NudC(Rv)) and ...[more]

PMID: 22026918

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Project description:Objectives This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: To estimate the diagnostic accuracy of Xpert MTB/XDR for the detection of pulmonary tuberculosis in people with signs and symptoms of pulmonary tuberculosis. To estimate the diagnostic accuracy of Xpert MTB/XDR for resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin in people irrespective of rifampicin resistance and people with detected rifampicin resistance. In these populations, pulmonary tuberculosis will have been detected by Xpert MTB/XDR (as it is a reflex test). Such populations typically will have received prior testing verifying tuberculosis with another WHO‐approved test. Secondary objectives To compare the diagnostic accuracy of Xpert MTB/XDR by direct testing versus indirect testing (whereby Xpert MTB/XDR is performed on a Mycobacterium tuberculosis isolate grown from culture). To investigate the effects of potential sources of heterogeneity on test accuracy. For pulmonary tuberculosis, potential sources include HIV status, smear status, history of tuberculosis, treatment status (no treatment or currently on treatment), and treatment response status (culture conversion, yes or no). For drug resistance, potential sources include the type of reference standard and history of tuberculosis treatment. In addition, for fluoroquinolone resistance, a potential source of heterogeneity is the specific drug (e.g. ofloxacin or moxifloxacin) used in the phenotypic culture‐based DST (pDST) reference standard. We will also consider whether the WHO‐recommended critical drug concentration was used for the pDST reference standard (WHO Critical Concentrations 2018; WHO Critical Concentrations 2021). Regarding previously treated people, these investigations are important questions for clinical practice. For tuberculosis detection, studies have highlighted the challenges in interpreting Xpert MTB/RIF‐positive and Xpert Ultra‐positive results in previously treated people (Mishra 2020; Theron 2016a). As mentioned, for detection of drug resistance, previous treatment may increase the likelihood of having drug resistance.

Dataset Information

Comparative analysis of mycobacterial NADH pyrophosphatase isoforms reveals a novel mechanism for isoniazid and ethionamide inactivation.

Publications

Comparative analysis of mycobacterial NADH pyrophosphatase isoforms reveals a novel mechanism for isoniazid and ethionamide inactivation.

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