The Value of the inhA Mutation Detection in Predicting Ethionamide Resistance Using Melting Curve Technology

Song, Yanhua; Wang, Guirong; Li, Qiang; Liu, Rongmei; Ma, Li; Gao, Mengqiu

doi:10.2147/idr.s268799

Cited by 7 publications

(3 citation statements)

References 17 publications

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“…These results suggest that, currently, mutation test results should be carefully evaluated, because ethA and fabG1 mutant strains could still be sensitive to ethionamide and may be effective for ethionamide treatment. This finding is in line with a study by Song and colleagues [ 37 ].…”

Section: Discussionsupporting

confidence: 94%

Genotypic and phenotypic comparison of drug resistance profiles of clinical multidrug-resistant Mycobacterium tuberculosis isolates using whole genome sequencing in Latvia

Vīksna,

Sadovska,

Berge

et al. 2023

BMC Infect Dis

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Background Multidrug-resistant tuberculosis (MDR–TB) remains a major public health problem in many high tuberculosis (TB) burden countries. Phenotypic drug susceptibility testing (DST) take several weeks or months to result, but line probe assays and Xpert/Rif Ultra assay detect a limited number of resistance conferring gene mutations. Whole genome sequencing (WGS) is an advanced molecular testing method which theoretically can predict the resistance of M. tuberculosis (Mtb) isolates to all anti-TB agents through a single analysis. Methods Here, we aimed to identify the level of concordance between the phenotypic and WGS-based genotypic drug susceptibility (DS) patterns of MDR–TB isolates. Overall, data for 12 anti-TB medications were analyzed. Results In total, 63 MDR–TB Mtb isolates were included in the analysis, representing 27.4% of the total number of MDR–TB cases in Latvia in 2012–2014. Among them, five different sublineages were detected, and 2.2.1 (Beijing group) and 4.3.3 (Latin American-Mediterranean group) were the most abundant. There were 100% agreement between phenotypic and genotypic DS pattern for isoniazid, rifampicin, and linezolid. High concordance rate (> 90%) between phenotypic and genotypic DST results was detected for ofloxacin (93.7%), pyrazinamide (93.7%) and streptomycin (95.4%). Phenotypic and genotypic DS patterns were poorly correlated for ethionamide (agreement 56.4%), ethambutol (85.7%), amikacin (82.5%), capreomycin (81.0%), kanamycin (85.4%), and moxifloxacin (77.8%). For capreomycin, resistance conferring mutations were not identified in several phenotypically resistant isolates, and, in contrary, for ethionamide, ethambutol, amikacin, kanamycin, and moxifloxacin the resistance-related mutations were identified in several phenotypically sensitive isolates. Conclusions WGS is a valuable tool for rapid genotypic DST for all anti-TB agents. For isoniazid and rifampicin phenotypic DST potentially can be replaced by genotypic DST based on 100% agreement between the tests. However, discrepant results for other anti-TB agents limit their prescription based solely on WGS data. For clinical decision, at the current level of knowledge, there is a need for combination of genotypic DST with modern, validated phenotypic DST methodologies for those medications which did not showed 100% agreement between the methods.

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Section: Discussionsupporting

confidence: 94%

Genotypic and phenotypic comparison of drug resistance profiles of clinical multidrug-resistant Mycobacterium tuberculosis isolates using whole genome sequencing in Latvia

Vīksna,

Sadovska,

Berge

et al. 2023

BMC Infect Dis

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“…Both enzymes form a stable covalent adduct with nicotinamide adenine dinucleotide (NAD) 46 that inhibits InhA, which is involved in mycolic acid biosynthesis. 37,45,47,48 As DA-CB may also inhibit mycolic acid biosynthesis, we investigated the cellular processes that DA-CB alters by employing a multi-omics approach to characterize the metabolome, proteome, and lipidome of Msm. Statistical analysis of these individual omics data sets showed a significant alteration due to DA-CB.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…In contrast, INH is activated by the peroxidase KatG. Both enzymes form a stable covalent adduct with nicotinamide adenine dinucleotide (NAD) that inhibits InhA, which is involved in mycolic acid biosynthesis. ,,, …”

Section: Resultsmentioning

confidence: 99%

Multi-omics Investigation into the Mechanism of Action of an Anti-tubercular Fatty Acid Analogue

et al. 2022

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The mechanism of action (MoA) of a clickable fatty acid analogue 8-(2-cyclobuten-1-yl)octanoic acid (DA-CB) has been investigated for the first time. Proteomics, metabolomics, and lipidomics were combined with a network analysis to investigate the MoA of DA-CB against Mycobacterium smegmatis (Msm). The metabolomics results showed that DA-CB has a general MoA related to that of ethionamide (ETH), a mycolic acid inhibitor that targets enoyl-ACP reductase (InhA), but DA-CB likely inhibits a step downstream from InhA. Our combined multi-omics approach showed that DA-CB appears to disrupt the pathway leading to the biosynthesis of mycolic acids, an essential mycobacterial fatty acid for both Msm and Mycobacterium tuberculosis (Mtb). DA-CB decreased keto-meromycolic acid biosynthesis. This intermediate is essential in the formation of mature mycolic acid, which is a key component of the mycobacterial cell wall in a process that is catalyzed by the essential polyketide synthase Pks13 and the associated ligase FadD32. The multi-omics analysis revealed further collateral alterations in bacterial metabolism, including the overproduction of shorter carbon chain hydroxy fatty acids and branched chain fatty acids, alterations in pyrimidine metabolism, and a predominate downregulation of proteins involved in fatty acid biosynthesis. Overall, the results with DA-CB suggest the exploration of this and related compounds as a new class of tuberculosis (TB) therapeutics. Furthermore, the clickable nature of DA-CB may be leveraged to trace the cellular fate of the modified fatty acid or any derived metabolite or biosynthetic intermediate.

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A review on enzyme complexes of electron transport chain from Mycobacterium tuberculosis as promising drug targets

Anand

Akhter

2022

International Journal of Biological Macromolecules

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The Value of the inhA Mutation Detection in Predicting Ethionamide Resistance Using Melting Curve Technology

Cited by 7 publications

References 17 publications

Genotypic and phenotypic comparison of drug resistance profiles of clinical multidrug-resistant Mycobacterium tuberculosis isolates using whole genome sequencing in Latvia

Genotypic and phenotypic comparison of drug resistance profiles of clinical multidrug-resistant Mycobacterium tuberculosis isolates using whole genome sequencing in Latvia

Multi-omics Investigation into the Mechanism of Action of an Anti-tubercular Fatty Acid Analogue

A review on enzyme complexes of electron transport chain from Mycobacterium tuberculosis as promising drug targets

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