The Bewildering Antitubercular Action of Pyrazinamide

Lamont, Elise A.; Dillon, Nicholas; Baughn, Anthony D.

doi:10.1128/mmbr.00070-19

Cited by 53 publications

(53 citation statements)

References 151 publications

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“…Nevertheless, including all 122 group C mutations would increase the sensitivity to 85% (95% CI, 84% to 86%) while reducing the specificity only marginally to 98% (95% CI, 97% to 99%) ( Table 1). This supports earlier findings that the vast majority of nonsynonymous mutations in pncA cause resistance (1,17).…”

supporting

confidence: 92%

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How To Optimally Combine Genotypic and Phenotypic Drug Susceptibility Testing Methods for Pyrazinamide

Köser

Cirillo

Miotto

2020

Antimicrob Agents Chemother

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False susceptible phenotypic drug-susceptibility testing (DST) results for pyrazinamide due to mutations with MICs close to the critical concentration (CC) confound the classification of pncA resistance mutations, leading to an underestimate of the specificity of genotypic DST. This could be minimised by basing treatment decisions on well-understood mutations and by adopting an area of technical uncertainty for phenotypic DST rather than only testing the CC, as is current practice for the Mycobacterium tuberculosis complex.

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supporting

confidence: 92%

“…Pyrazinamide (PZA) is critical for the treatment of tuberculosis (TB) ( 1 ). Because the Bactec MGIT system has a higher random rate of false resistance to PZA than to other drugs, phenotypic drug-susceptibility testing (pDST) is not carried out at all in many countries with a high incidence of TB ( 2 , 3 ).…”

Section: Introductionmentioning

confidence: 99%

How To Optimally Combine Genotypic and Phenotypic Drug Susceptibility Testing Methods for Pyrazinamide

Köser

Cirillo

Miotto

2020

Antimicrob Agents Chemother

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“…This leads to a lethal alteration of membrane permeability; however, the exact mechanism by which this occurs is not yet known (3). It is important to note that other recent studies found that extracellular acid pH is not required in order for PZA/POA achieve its lethal effect (4,5,6). This confirms that the real mechanism of action of PZA is actually more complicated than previously thought, and further research is required.…”

Section: Introductionsupporting

confidence: 61%

EXPRESSION OFMycobacterium tuberculosisRpsA INMycobacterium smegmatisINCREASES SUSCEPTIBILITY TO PYRAZINAMIDE

Antiparra

Santos

Toledo

et al. 2020

Preprint

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Pyrazinamide (PZA) is one of the most important drugs used in combined antituberculous therapy. After the drug enters Mycobacterium tuberculosis it is hydrolyzed by pyrazinamidase (PZAse) to the bactericidal molecule pyrazinoic acid (POA).Ribosomal protein S1 (RpsA) was recently identified as a possible target of PZA based on its binding activity to POA and capacity to inhibit trans-translation. However, its role is not completely understood. It has been proposed thatMycobacterium smegmatis RpsA is not capable of binding POA, unlike M. tuberculosis RpsA. This may be due to the different amino acid sequence in the carboxy-terminal region of the two molecules: in M. smegmatis RpsA it is much closer to the sites that may interact with POA than in M. tuberculosis RpsA. These differences could be contributing, along with the presence of highly active POA efflux, to the natural resistance to PZA in M. smegmatis. To further understand the mechanisms of action of PZA and the role of RpsA in PZA susceptibility, we evaluated the effect of complementing M. tuberculosis RpsA expression in M. smegmatis using pNIT mycobacterial non-integrative expression vector and then performed a PZA susceptibility test determining the minimum inhibitory concentration (MIC) of PZA. It was expected that chimeric ribosomes comprising M.tuberculosis RpsA may be present and may affect PZA susceptibility.Our results showed a reduction in PZA MIC in M. smegmatis complemented with overexpressed M. tuberculosis RpsA compared to non-overexpressed M. smegmatis (468 µg/mL and >7500 µg/mL respectively).

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“…However, PZA pH-independent activity have also been reported and additional PZA/POA modes of action proposed 32,33,34 . For example, PZA also inhibits the biosynthesis of Coenzyme-A through inhibition of the aspartate decarboxylase PanD and enhancement of its degradation by the Clp protease system 35,36,37 .…”

Section: Introductionmentioning

confidence: 99%

Intracellular localisation ofMycobacterium tuberculosisaffects antibiotic efficacy

Santucci

Fearns

et al. 2020

Preprint

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To be effective, chemotherapy against tuberculosis (TB) must kill the intracellular population of Mycobacterium tuberculosis (Mtb). However, how host cell environments affect antibiotic accumulation and efficacy remains elusive. Pyrazinamide (PZA) is a key antibiotic against TB, yet its behaviour is not fully understood. Here, by using correlative light, electron, and ion microscopy to image PZA at the subcellular level, we investigated how human macrophage environments affect PZA activity. We discovered that PZA accumulates heterogeneously between individual bacteria in multiple host cell environments. Crucially, Mtb phagosomal localisation and acidification increase PZA accumulation and efficacy. By imaging two antibiotics commonly used in combined TB therapy, we showed that bedaquiline (BDQ) significantly enhances PZA accumulation by a host cell mediated mechanism. Thus, intracellular localisation and specific microenvironments affect PZA accumulation and efficacy; explaining the potent in vivo efficacy compared to its modest in vitro activity and the critical contribution to TB combination chemotherapy.

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The Bewildering Antitubercular Action of Pyrazinamide

Cited by 53 publications

References 151 publications

How To Optimally Combine Genotypic and Phenotypic Drug Susceptibility Testing Methods for Pyrazinamide

How To Optimally Combine Genotypic and Phenotypic Drug Susceptibility Testing Methods for Pyrazinamide

EXPRESSION OFMycobacterium tuberculosisRpsA INMycobacterium smegmatisINCREASES SUSCEPTIBILITY TO PYRAZINAMIDE

Intracellular localisation ofMycobacterium tuberculosisaffects antibiotic efficacy

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