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Mechanisms of Pyrazinamide Action and Resistance

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  • Authors: Ying Zhang1, Wanliang Shi3, Wenhong Zhang4, Denis Mitchison5
  • Editors: Graham F. Hatfull6, William R. Jacobs Jr.7
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205; 2: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China; 3: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205; 4: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China; 5: Centre for Infection, St. George's, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom; 6: University of Pittsburgh, Pittsburgh, PA; 7: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY
  • Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0023-2013
  • Received 01 August 2013 Accepted 27 August 2013 Published 18 July 2014
  • Y. Zhang, yzhang@jhsph.edu
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  • Abstract:

    Pyrazinamide (PZA) is a unique antituberculosis (anti-TB) drug that plays a key role in shortening TB therapy. PZA kills nonreplicating persisters that other TB drugs fail to kill, which makes it an essential drug for inclusion in any drug combinations for treating drug-susceptible and drug-resistant TB such as multidrug-resistant TB. PZA acts differently from common antibiotics by inhibiting multiple targets such as energy production, trans-translation, and perhaps pantothenate/coenzyme A required for persister survival. Resistance to PZA is mostly caused by mutations in the gene encoding pyrazinamidase, which is involved in conversion of the prodrug PZA to the active form pyrazinoic acid. Mutations in the drug target ribosomal protein S1 (RpsA) are also found in some PZA-resistant strains. The recent finding that mutations are found in some PZA-resistant strains without or mutations may suggest a third PZA resistance gene and a potential new target of PZA. Current phenotype-based PZA susceptibility testing is not reliable due to false resistance; sequencing of the gene represents a more rapid, cost-effective, and reliable molecular test for PZA susceptibility testing and should be used for guiding improved treatment of multidrug-resistant and extensively multidrug-resistant TB. Finally, the story of PZA has important implications for not only TB therapy but also chemotherapy in general. PZA serves as a model prototype persister drug and hopefully a “tipping point” that inspires new efforts at developing a new type of antibiotic or drug that targets nonreplicating persisters for improved treatment of not only TB but also other persistent bacterial infections.

  • Citation: Zhang Y, Shi W, Zhang W, Mitchison D. 2014. Mechanisms of Pyrazinamide Action and Resistance. Microbiol Spectrum 2(4):MGM2-0023-2013. doi:10.1128/microbiolspec.MGM2-0023-2013.

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References

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2014-07-18
2017-05-28

Abstract:

Pyrazinamide (PZA) is a unique antituberculosis (anti-TB) drug that plays a key role in shortening TB therapy. PZA kills nonreplicating persisters that other TB drugs fail to kill, which makes it an essential drug for inclusion in any drug combinations for treating drug-susceptible and drug-resistant TB such as multidrug-resistant TB. PZA acts differently from common antibiotics by inhibiting multiple targets such as energy production, trans-translation, and perhaps pantothenate/coenzyme A required for persister survival. Resistance to PZA is mostly caused by mutations in the gene encoding pyrazinamidase, which is involved in conversion of the prodrug PZA to the active form pyrazinoic acid. Mutations in the drug target ribosomal protein S1 (RpsA) are also found in some PZA-resistant strains. The recent finding that mutations are found in some PZA-resistant strains without or mutations may suggest a third PZA resistance gene and a potential new target of PZA. Current phenotype-based PZA susceptibility testing is not reliable due to false resistance; sequencing of the gene represents a more rapid, cost-effective, and reliable molecular test for PZA susceptibility testing and should be used for guiding improved treatment of multidrug-resistant and extensively multidrug-resistant TB. Finally, the story of PZA has important implications for not only TB therapy but also chemotherapy in general. PZA serves as a model prototype persister drug and hopefully a “tipping point” that inspires new efforts at developing a new type of antibiotic or drug that targets nonreplicating persisters for improved treatment of not only TB but also other persistent bacterial infections.

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FIGURE 1

Conversion of nicotinamide and PZA to nicotinic acid and POA, respectively, by the enzyme PZase/nicotinamidase (PncA) encoded by the gene. doi:10.1128/microbiolspec.MGM2-0023-2013.f1

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0023-2013
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FIGURE 2

Mode of action of PZA. PZA enters tubercle bacilli by passive diffusion, where it is converted to POA by PZase/nicotinamidase encoded by the gene. POA then reaches the cell surface through passive diffusion and a weak (deficient) efflux mechanism. At acid pH, the protonated POA (HPOA) enters the cell in a pH-dependent manner by passive diffusion and then accumulates to high levels intracellularly and kills by multiple mechanisms including disruption of membrane energy production, inhibition of trans-translation, possibly inhibition of pantothenate and CoA biosynthesis, and other as yet unidentified mechanisms. doi:10.1128/microbiolspec.MGM2-0023-2013.f2

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0023-2013
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FIGURE 3

Diverse mutations scattered along the gene in PZA-resistant The mutations were obtained from the Drug Resistance Mutation Database (http://www.tbdreamdb.com). doi:10.1128/microbiolspec.MGM2-0023-2013.f3

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0023-2013
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TABLE 1

Increased PZA susceptibility of mutants with a defect in energy metabolism

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0023-2013

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