Host-Mediated Bioactivation of Pyrazinamide: Implications for Efficacy, Resistance, and Therapeutic Alternatives

Laura E. Via, Rada Savic, Danielle M. Weiner, Matthew D. Zimmerman, Brendan Prideaux, Scott M. Irwin, Eddie Lyon, Paul O'Brien, Pooja Gopal, Seokyong Eum, Myungsun Lee, Jean Philippe Lanoix, Noton K. Dutta, Tae Sun Shim, Jeong Su Cho, Wooshik Kim, Petros C. Karakousis, Anne Lenaerts, Eric Nuermberger, Clifton E. BarryVéronique Dartois

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Pyrazinamide has played a critical role in shortening therapy against drug-sensitive, drug-resistant, active, and latent tuberculosis (TB). Despite widespread recognition of its therapeutic importance, the sterilizing properties of this 60-year-old drug remain an enigma given its rather poor activity in vitro. Here we revisit long-standing paradigms and offer pharmacokinetic explanations for the apparent disconnect between in vitro activity and clinical impact. We show substantial host-mediated conversion of prodrug pyrazinamide (PZA) to the active form, pyrazinoic acid (POA), in TB patients and in animal models. We demonstrate favorable penetration of this pool of circulating POA from plasma into lung tissue and granulomas, where the pathogen resides. In standardized growth inhibition experiments, we show that POA exhibits superior in vitro potency compared to PZA, indicating that the vascular supply of host-derived POA may contribute to the in vivo efficacy of PZA, thereby reducing the apparent discrepancy between in vitro and in vivo activity. However, the results also raise the possibility that subinhibitory concentrations of POA generated by the host could fuel the emergence of resistance to both PZA and POA. In contrast to widespread expectations, we demonstrate good oral bioavailability and exposure in preclinical species in pharmacokinetic studies of oral POA. Baseline exposure of oral POA can be further increased by the xanthine oxidase inhibitor and approved gout drug allopurinol. These promising results pave the way for clinical investigations of oral POA as a therapeutic alternative or an add-on to overcome PZA resistance and salvage this essential TB drug.

Original languageEnglish (US)
Pages (from-to)203-214
Number of pages12
JournalACS Infectious Diseases
Volume1
Issue number5
DOIs
StatePublished - May 8 2015

Keywords

  • Mycobacterium tuberculosis
  • bioactivation
  • host metabolism
  • pyrazinamide
  • pyrazinoic acid

ASJC Scopus subject areas

  • Infectious Diseases

Fingerprint Dive into the research topics of 'Host-Mediated Bioactivation of Pyrazinamide: Implications for Efficacy, Resistance, and Therapeutic Alternatives'. Together they form a unique fingerprint.

  • Cite this

    Via, L. E., Savic, R., Weiner, D. M., Zimmerman, M. D., Prideaux, B., Irwin, S. M., Lyon, E., O'Brien, P., Gopal, P., Eum, S., Lee, M., Lanoix, J. P., Dutta, N. K., Shim, T. S., Cho, J. S., Kim, W., Karakousis, P. C., Lenaerts, A., Nuermberger, E., ... Dartois, V. (2015). Host-Mediated Bioactivation of Pyrazinamide: Implications for Efficacy, Resistance, and Therapeutic Alternatives. ACS Infectious Diseases, 1(5), 203-214. https://doi.org/10.1021/id500028m