title: Host-Mediated Bioactivation of Pyrazinamide: Implications for Efficacy, Resistance, and Therapeutic Alternatives.
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 longstanding 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.
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, NIH-NIAID, 33 North Drive, Bethesda, Maryland 20892-3206, United States.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Via
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California at San Francisco, 1550 Fourth Street, San Francisco, California 94143-2911, United States.
authors.forename: Rada
authors.initials: R
authors.lastname: Savic
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, NIH-NIAID, 33 North Drive, Bethesda, Maryland 20892-3206, United States.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Weiner
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, 225 Warren Street, Newark, New Jersey 07103, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Zimmerman
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, 225 Warren Street, Newark, New Jersey 07103, United States.
authors.forename: Brendan
authors.initials: B
authors.lastname: Prideaux
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, 200 West Lake Street, Ft. Collins, Colorado 80523-4629, United States.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Irwin
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, 200 West Lake Street, Ft. Collins, Colorado 80523-4629, United States.
authors.forename: Eddie
authors.initials: E
authors.lastname: Lyon
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, 225 Warren Street, Newark, New Jersey 07103, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: O'Brien
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, MD4A #05-01, 5 Science Drive 2, Singapore 117597.
authors.forename: Pooja
authors.initials: P
authors.lastname: Gopal
authors.affiliation: International Tuberculosis Research Center, 475-1 Gapo-dong, Masan, Kyeungsangnam-do 631-710, Republic of Korea.
authors.forename: Seokyong
authors.initials: S
authors.lastname: Eum
authors.affiliation: International Tuberculosis Research Center, 475-1 Gapo-dong, Masan, Kyeungsangnam-do 631-710, Republic of Korea.
authors.forename: Myungsun
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, Maryland 21287, United States.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lanoix
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, Maryland 21287, United States.
authors.forename: Noton K
authors.initials: NK
authors.lastname: Dutta
authors.affiliation: Asan Medical Center, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, Republic of Korea.
authors.forename: TaeSun
authors.initials: T
authors.lastname: Shim
authors.affiliation: Pusan National University Hospital, 305 Gudeok-Ro, Seo-Gu, Busan 602-739, Republic of Korea.
authors.forename: Jeong Su
authors.initials: JS
authors.lastname: Cho
authors.affiliation: National Medical Center, 245 Euljiro, Jung-gu, Seoul 100-799, Republic of Korea.
authors.forename: Wooshik
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, Maryland 21287, United States.
authors.forename: Petros C
authors.initials: PC
authors.lastname: Karakousis
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, 200 West Lake Street, Ft. Collins, Colorado 80523-4629, United States.
authors.forename: Anne
authors.initials: A
authors.lastname: Lenaerts
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, Maryland 21287, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Nuermberger
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, NIH-NIAID, 33 North Drive, Bethesda, Maryland 20892-3206, United States.
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, 225 Warren Street, Newark, New Jersey 07103, United States.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dartois
keywords: Mycobacterium tuberculosis; bioactivation; host metabolism; pyrazinamide; pyrazinoic acid