A New Approach for Pyrazinamide Susceptibility Testing in<i>Mycobacterium tuberculosis</i>

Zimic, Mirko; Loli, Sebastian; Gilman, Robert H.; Gutiérrez, Andres H.; Fuentes, Patricia; Cotrina, Milagros; Kirwan, Daniela E.; Sheen, Patricia

doi:10.1089/mdr.2011.0207

Cited by 20 publications

(21 citation statements)

References 16 publications

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“…From the 20 pncA mutated strains, 14 isolates were selected from our strains collection and previously described 19–21 and the remaining 6 were new isolates. From the 10 pncA wild type, 7 isolates were selected from our strain collection because they were resistant to PZA.…”

Section: Methodsmentioning

confidence: 99%

“…10,20 Recently, other studies have reported that the POA efflux rate was more predictive of PZA resistance (61%) than the PZAse activity with a high sensitivity and specificity, making it an important predictor of PZA resistance in M. tuberculosis . 19–21 This evidence suggests that other factors should be present to account for the remaining unexplained variability of PZA resistance. Although it has not been proved, it is evident and likely that the POA efflux rate at least depends on the PZAse activity, the intracellular PZAse concentration, the efficiency of the efflux pump system, and the concentration of efflux pumps.…”

Section: Introductionmentioning

confidence: 95%

“…Although it has not been proved, it is evident and likely that the POA efflux rate at least depends on the PZAse activity, the intracellular PZAse concentration, the efficiency of the efflux pump system, and the concentration of efflux pumps. Whilst the importance of the POA efflux rate to the susceptibility to PZA is recognized and its quantitative effect has been shown to be significant, 19–21 the identity of the POA efflux pump system is still unknown.…”

Section: Introductionmentioning

confidence: 99%

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pncA gene expression and prediction factors on pyrazinamide resistance in Mycobacterium tuberculosis

et al. 2013

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Summary Background Mutations in the pyrazinamidase (PZAse) coding gene, pncA, have been considered as the main cause of pyrazinamide (PZA) resistance in Mycobacterium tuberculosis. However, recent studies suggest there is no single mechanism of resistance to PZA. The pyrazinoic acid (POA) efflux rate is the basis of the PZA susceptibility Wayne test, and its quantitative measurement has been found to be a highly sensitive and specific predictor of PZA resistance. Based on biological considerations, the POA efflux rate is directly determined by the PZAse activity, the level of pncA expression, and the efficiency of the POA efflux pump system. Objective This study analyzes the individual and the adjusted contribution of PZAse activity, pncA expression and POA efflux rate on PZA resistance. Methods Thirty M. tuberculosis strains with known microbiological PZA susceptibility or resistance were analyzed. For each strain, PZAse was recombinantly produced and its enzymatic activity measured. The level of pncA mRNA was estimated by quantitative RT-PCR, and the POA efflux rate was determined. Mutations in the pncA promoter were detected by DNA sequencing. All factors were evaluated by multiple regression analysis to determine their adjusted effects on the level of PZA resistance. Findings Low level of pncA expression associated to mutations in the pncA promoter region was observed in pncA wild type resistant strains. POA efflux rate was the best predictor after adjusting for the other factors, followed by PZAse activity. These results suggest that tests which rely on pncA mutations or PZAse activity are likely to be less predictive of real PZA resistance than tests which measure the rate of POA efflux. This should be further analyzed in light of the development of alternate assays to determine PZA resistance.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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pncA gene expression and prediction factors on pyrazinamide resistance in Mycobacterium tuberculosis

et al. 2013

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“…PZAse malfunction is caused by mutations in its coding gene ( pncA ) [11], as well as in its promoter region compromising the expression of the protein [12], resulting in lack of conversion of PZA into POA [13]. Previous studies have demonstrated that POA efflux rate varies amongst M. tuberculosis strains [14] and its quantitative variability is significantly associated with the level of PZA resistance [15]. …”

Section: Introductionmentioning

confidence: 99%

A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance

et al. 2017

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BackgroundTuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear.ResultsWe genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping. We analyzed the association between PZA resistance with non-synonymous mutations and specific genes.We found mutations in pncA and novel genes significantly associated with PZA resistance in strains without pncA mutations. These included genes related to transportation of metal ions, pH regulation and immune system evasion.ConclusionsThese results suggest potential alternate mechanisms of PZA resistance that have not been found in other populations, supporting that the antibacterial activity of PZA may hit multiple targets.Electronic supplementary materialThe online version of this article (10.1186/s12864-017-4146-z) contains supplementary material, which is available to authorized users.

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“…Although number of studies suggest that PZA resistance is not caused by a single mechanism, mutations in the pncA gene are considered as the main mechanism of PZA resistance in M. tuberculosis [4]. The lack of reliable culture-based methods which require an acidic condition and high cost of the molecular techniques makes the testing of PZA resistance generally very difficult to perform [5]. It is very important to develop rapid and accurate drug susceptibility testing (DST) to prevent the spread of multi-drug resistant (MDR)-TB as well as extremely drug resistant (XDR)-TB.…”

Section: Introductionmentioning

confidence: 99%

High Resolution Melting Curve Analysis for Rapid Detection of Pyrazinamide Resistance in <i>Mycobacterium tuberculosis</i> Clinical Isolates

Osman¹,

Ismail²,

Osman³

et al. 2016

JTR

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A New Approach for Pyrazinamide Susceptibility Testing inMycobacterium tuberculosis

Cited by 20 publications

References 16 publications

pncA gene expression and prediction factors on pyrazinamide resistance in Mycobacterium tuberculosis

pncA gene expression and prediction factors on pyrazinamide resistance in Mycobacterium tuberculosis

A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance

High Resolution Melting Curve Analysis for Rapid Detection of Pyrazinamide Resistance in <i>Mycobacterium tuberculosis</i> Clinical Isolates

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A New Approach for Pyrazinamide Susceptibility Testing inMycobacterium tuberculosis

Cited by 20 publications

References 16 publications

pncA gene expression and prediction factors on pyrazinamide resistance in Mycobacterium tuberculosis

pncA gene expression and prediction factors on pyrazinamide resistance in Mycobacterium tuberculosis

A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance

High Resolution Melting Curve Analysis for Rapid Detection of Pyrazinamide Resistance in &lt;i&gt;Mycobacterium tuberculosis&lt;/i&gt; Clinical Isolates

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High Resolution Melting Curve Analysis for Rapid Detection of Pyrazinamide Resistance in <i>Mycobacterium tuberculosis</i> Clinical Isolates