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Pyrazinamide
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Pyrazinamide is a prodrug that is converted into the active form, pyrazinoic acid, within M. tuberculosis by the action of pyrazinamidase, a nicotinamidase encoded by the gene pncA (Scorpio and Zhang, 1996). Pyrazinoic acid accumulates intracellularly at acid pH, suggesting a possible mechanism for the particular activity of pyrazinamide within acidic environments (Zhang et al., 2014). Mutations in the pncA gene of M. tuberculosis result in resistance to pyrazinamide, and many different mutations in pncA have been described, including in the upstream intergenic region (Scorpio et al., 1997; Wade and Zhang, 2004). M. bovis is naturally resistant to pyrazinamide because all strains have a mutation in pncA. The absence of pyrazinamidase activity can be used to detect pyrazinamide resistance in M. tuberculosis (Morlock et al., 2000). Strains of M. tuberculosis with a wild-type pncA sequence have been described that have phenotypically low-level pyrazinamide resistance but retain pyrazinamidase activity, and efflux mechanisms are also thought to play a role in mediating such resistance (Cheng et al., 2000).
Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Peter D O Davies, Stephen B Gordon, Geraint Davies, Clinical Tuberculosis, 2014
Abdullah Alsultan, Charles A. Peloquin
PZA is a synthetic agent with a molecular weight (MW) of 123 [79]. PZA is a pro-drug activated by the pyrazinamidase enzyme in mycobacteria. PZA has useful activity only against M. tuberculosis and Mycobacterium africanum. M. bovis and the other mycobacteria are naturally resistant [4]. Understanding the mechanism of action has been problematic. Pyrazinoic acid appears to be the active moiety, although it is only the pyrazinoic acid created within tubercle bacilli that appears to be active because the organisms do not appear to take up significant amounts of the acid from their surroundings [4,80–82]. Some reports have suggested that PZA acts against fatty acid synthesis, as does 5-chloro-PZA, by inhibiting fatty acid synthase I (FAS-I) and this debate continues [83,84]. Other reports have suggested other mechanisms as inhibiting protein translation by targeting ribosomal protein S1, depletion of cellular adenosine triphosphate (ATP) and/or disruption of membrane transport [85,86]. It may be that the accumulation of inorganic acids within the organisms produces a stress that they cannot withstand [80–82]. Mutations in the pncA gene that encodes the pyrazinamidase enzyme are associated with PZA resistance [87].
Molecular identification of mutations conferring resistance to rifampin, isoniazid and pyrazinamide among Mycobacterium tuberculosis isolates from Iran
Published in Journal of Chemotherapy, 2020
Ahad Ali Haratiasl, Gholamreza Hamzelou, Sirus Amini, Jalil Kardan-Yamchi, Mehri Haeili, Fereshteh Heidari, Mohammad Mehdi Feizabadi
Mutations at pncA is the most common mechanism accounting for PZA resistance, being identified in over 80% of PZA-resistant isolates. The mutations are commonly concentrated at 3 regions (codons 3–17, 61–85, and 132–142) that contain the PZase active and metal-binding sites. Nevertheless, mutations in the pncA promoter region can also affect the PZase activity by disturbing pncA translation.32 While a small group of resistant MTB isolates with a low level of resistance to PZA do not show any mutation in pncA, mutations can be seen in other genes, such as rpsA, which are less likely to interfere with pyrazinamide resistance.8 Up to 10% of the PZA-R cases have been reported to carry no mutation associated with phenotypic resistance.32 In this study, sequencing of pncA gene in 11 pyrazinamide resistant strains showed only one change (Δ416 T), and no alteration was observed in the gene sequences in the remaining strains. This condition can be attributed to the concentration of pyrazinamide (25 μg/mL) used in this study to detect antibiotic susceptibility which was lower than that used by other studies. 33 Therefore, pyrazinamide resistant strains in this study may be susceptible at higher concentrations and only one isolate might be real resistant phenotype showing the genotypic mutation in pncA. Also, it can be related to heteroresistance or the occurrence of mutations in other genes (panD, rpsA) that were not studied in this project as explained by Jim Werngren et al.34
Management of complex tuberculosis cases: a focus on drug-resistant tuberculous meningitis
Published in Expert Review of Anti-infective Therapy, 2018
Ravindra Kumar Garg, Imran Rizvi, Hardeep Singh Malhotra, Ravi Uniyal, Neeraj Kumar
Para-aminosalicylic acid and ethambutol are not effective drugs to treat multidrug-resistant tuberculous meningitis as they have no or low penetration in the CNS. Para-aminosalicylic acid penetration may be increased in CSF if it is given in entirety as a single daily dose. Imipenem–cilastatin, meropenem, and amoxicillin-clavulanate have never been tested in tuberculous meningitis and, therefore, cannot be considered as a viable treatment option. Bedaquiline and delamanid are two novel drugs that are being tested. A study in rats showed penetration of delamanid in CSF. Human data about its CSF penetration is needed before delamanid is tried for drug-resistant tuberculous meningitis. [106] Imipenem has good CSF penetration, but its role in tuberculous meningitis is unexplored. Children with bacterial meningitis treated with Imipenem had a risk of recurrent seizures [107]. Pyrazinamide reduces the relapse rates of isoniazid-resistant pulmonary tuberculosis to 1% if administered continuously throughout 6 months, as opposed to 7% when given only for 2 months [108]. It is an important drug in tuberculous meningitis due to its excellent CSF penetration profile, but multidrug-resistant M. tuberculosis isolates may also be resistant for pyrazinamide. Mutations in the pncA gene, that confers pyrazinamide resistance, were demonstrated in 70% of multidrug-resistant and 96% of extensively drug-resistant M. tuberculosis isolates [109].
Retrospective evaluation of routine whole genome sequencing of Mycobacterium tuberculosis at the Belgian National Reference Center, 2019
Published in Acta Clinica Belgica, 2022
Karine Soetaert, Pieter-Jan Ceyssens, Samira Boarbi, Bert Bogaerts, Thomas Delcourt, Kevin Vanneste, Sigrid C.J. De Keersmaecker, Nancy H.C. Roosens, Alexandra Vodolazkaia, Marina Mukovnikova, Vanessa Mathys
The lower sensitivity for predicting resistance to PZA is explained by the large number of potential resistance mutations in pncA and its promoter [27]. In the new WHO catalogue, group 1 mutations only had a combined sensitivity of 56.8% (95% CI, 54.8–58.8%). Therefore, the WHO added a new expert rule which says that all non-synonymous mutations in pncA should be assumed to confer resistance if they occur in a RIF-resistant isolate [10]. Adding to this issue, false in vitro resistance to PZA is known to happen with phenotypic techniques. Therefore, false phenotypic PZA resistance should be suspected especially in case of mono-resistance to PZA and a non-bovine species identification [28–31].