<i>pncA</i> Gene Mutations Associated with Pyrazinamide Resistance in Drug-Resistant Tuberculosis, South Africa and Georgia

Allana, Salim; Shashkina, Elena; Mathema, Barun; Bablishvili, Nino; Tukvadze, Nestani; Shah, Nishant K.; Kempker, Russell R.; Blumberg, Henry M.; Moodley, Prashini; Mlisana, Koleka; Brust, James C.M.; Gandhi, Neel R.

doi:10.3201/eid2303.161034

Cited by 34 publications

(30 citation statements)

References 12 publications

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“…In contrast, PZA resistance was higher in isolates with concurrent resistance to FQ without SLI resistance (pre-XDR). Resistance to SLI had no significant influence, although numbers were low, yet this concurs with other studies [ 33 , 34 ].…”

Section: Discussionsupporting

confidence: 92%

Half of rifampicin-resistant Mycobacterium tuberculosis complex isolated from tuberculosis patients in Sub-Saharan Africa have concomitant resistance to pyrazinamide

et al. 2017

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BackgroundBesides inclusion in 1st line regimens against tuberculosis (TB), pyrazinamide (PZA) is used in 2nd line anti-TB regimens, including in the short regimen for multidrug-resistant TB (MDR-TB) patients. Guidelines and expert opinions are contradictory about inclusion of PZA in case of resistance. Moreover, drug susceptibility testing (DST) for PZA is not often applied in routine testing, and the prevalence of resistance is unknown in several regions, including in most African countries.MethodsSix hundred and twenty-three culture isolates from rifampicin-resistant (RR) patients were collected in twelve Sub-Saharan African countries. Among those isolates, 71% were from patients included in the study on the Union short-course regimen for MDR-TB in Benin, Burkina Faso, Burundi, Cameroon, Central Africa Republic, the Democratic Republic of the Congo, Ivory Coast, Niger, and Rwanda PZA resistance, and the rest (29%) were consecutive isolates systematically stored from 2014–2015 in Mali, Rwanda, Senegal, and Togo. Besides national guidelines, the isolates were tested for PZA resistance through pncA gene sequencing.ResultsOver half of these RR-TB isolates (54%) showed a mutation in the pncA gene, with a significant heterogeneity between countries. Isolates with fluoroquinolone resistance (but not with injectable resistance or XDR) were more likely to have concurrent PZA resistance. The pattern of mutations in the pncA gene was quite diverse, although some isolates with an identical pattern of mutations in pncA and other drug-related genes were isolated from the same reference center, suggesting possible transmission of these strains.ConclusionSimilar to findings in other regions, more than half of the patients having RR-TB in West and Central Africa present concomitant resistance to PZA. Further investigations are needed to understand the relation between resistance to PZA and resistance to fluoroquinolones, and whether continued use of PZA in the face of PZA resistance provides clinical benefit to the patients.

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Section: Discussionsupporting

confidence: 92%

Half of rifampicin-resistant Mycobacterium tuberculosis complex isolated from tuberculosis patients in Sub-Saharan Africa have concomitant resistance to pyrazinamide

et al. 2017

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“…Thus, loss-of-function mutations in pncA represent the primary mechanism of PZA resistance in clinical isolates. Diverse pncA mutations, including single and multi-nucleotide polymorphisms and indels, have been reported in PZA resistant clinical isolates along the entire 561 base pair gene length [26,27] . Recently, Yadon et al [28] created a comprehensive library of PncA polymorphisms through saturating mutagenesis and identified over 300 substitutions, some of which were previously reported in clinical isolates, that conferred PZA resistance in vitro and in vivo.…”

Section: Proposed Molecular Targets For Pzamentioning

confidence: 99%

Impact of the host environment on the antitubercular action of pyrazinamide

Lamont

Baughn

2019

eBioMedicine

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a b s t r a c tPyrazinamide remains the only drug in the tuberculosis pharmacopeia to drastically shorten first-line therapy from nine to six months. Due to its unparalleled ability to sterilize non-replicating bacilli and reduce relapse rates, PZA is expected to be irreplaceable in future therapies against tuberculosis. While the molecular target of PZA is unclear, recent pharmacokinetic studies using small animal models and patient samples have highlighted the importance of host metabolism and immune responses in PZA efficacy. Delineating which host factors are important for PZA action will be integral to the design of next-generation therapies to shorten current TB drug regimens as well as to overcome treatment limitations in some patients. In this review, we discuss evidence for influence of the host environment on PZA activity, targets for PZA mechanism of action, recent studies in PZA pharmacokinetics, PZA antagonism and synergy with other first-line anti-TB drugs, and implications for future research.

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“…Its importance is based on its in vivo sterilizing effect that permits killing of persistent bacilli [18]. PZA is frequently used in both first-and second-line treatment regimens [19][20][21]. The incorporation of PZA into TB treatment regimens in the 1960s enabled the duration of first-line treatment to be reduced from nine to 12 months down to six months [22].…”

Section: Introductionmentioning

confidence: 99%

Molecular Specific and Sensitive Detection of Pyrazinamide and Its Metabolite Pyrazinoic Acid by Means of Surface Enhanced Raman Spectroscopy Employing In Situ Prepared Colloids

et al. 2019

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The prodrug pyrazinamide (PZA) is metabolized by the mycobacteria to pyrazinoic acid (POA), which is expelled into the extracellular environment. PZA resistance is highly associated to a lack of POA efflux. Thus, by detecting a reduction of the concentration of POA in the extracellular environment, by means of lab-on-a-chip (LoC)-SERS (surface-enhanced Raman spectroscopy), an alternative approach for the discrimination of PZA resistant mycobacteria is introduced. A droplet-based microfluidic SERS device has been employed to illustrate the potential of the LoC-SERS method for the discrimination of PZA resistant mycobacteria. The two analytes were detected discretely in aqueous solution with a limit of detection of 27 µm for PZA and 21 µm for POA. The simultaneous detection of PZA and POA in aqueous mixtures could be realized within a concentration range from 20 μm to 50 μm for PZA and from 50 μm to 80 μm for POA.

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pncA Gene Mutations Associated with Pyrazinamide Resistance in Drug-Resistant Tuberculosis, South Africa and Georgia

Cited by 34 publications

References 12 publications

Half of rifampicin-resistant Mycobacterium tuberculosis complex isolated from tuberculosis patients in Sub-Saharan Africa have concomitant resistance to pyrazinamide

Half of rifampicin-resistant Mycobacterium tuberculosis complex isolated from tuberculosis patients in Sub-Saharan Africa have concomitant resistance to pyrazinamide

Impact of the host environment on the antitubercular action of pyrazinamide

Molecular Specific and Sensitive Detection of Pyrazinamide and Its Metabolite Pyrazinoic Acid by Means of Surface Enhanced Raman Spectroscopy Employing In Situ Prepared Colloids

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