title: Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis.
abstract: Analog development of existing drugs and direct drug delivery to the lungs by inhalation as treatments for multiple and extensively drug resistant (MDR and XDR) tuberculosis (TB) represent new therapeutic strategies. Pyrazinamide (PZA) is critical to drug sensitive TB therapy and is included in regimens for MDR TB. However, PZA-resistant Mycobacterium tuberculosis (Mtb) strains threaten its use. Pyrazinoic acid esters (PAEs) are PZA analogs effective against Mtb in vitro, including against the most common PZA resistant strains. However, PAEs require testing for TB efficacy in animal models.
  
  
  
  PAEs were delivered daily as aqueous dispersions from a vibrating mesh nebulizer to Mtb infected guinea pigs for 4 weeks in a regimen including orally administered first-line TB drugs.
  
  
  
  PAEs tested as a supplement to oral therapy significantly reduced the organ bacterial burden in comparison to infected, untreated control animals. Thus, PAE aerosol therapy is a potentially significant addition to the regimen for PZA resistant MDR-TB and XDR-TB treatment. Interestingly, low dose oral PZA treatment combined with standard therapy also reduced bacterial burden. This observation may be important for PZA susceptible disease treatment.
  
  
  
  The present study justifies further evaluation of PZA analogs and their lung delivery to treat TB.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
authors.forename: E F
authors.initials: EF
authors.lastname: Young
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
authors.forename: E
authors.initials: E
authors.lastname: Perkowski
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
authors.forename: S
authors.initials: S
authors.lastname: Malik
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Hayden
authors.affiliation: RTI International, 3040 Cornwallis Road, Research Triangle Park, North Carolina, 27709, USA.
authors.forename: P G
authors.initials: PG
authors.lastname: Durham
authors.affiliation: Department of Chemistry, University of Albany, State University of New York, Albany, New York, 12222, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Department of Chemistry, University of Albany, State University of New York, Albany, New York, 12222, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Welch
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA. miriam_braunstein@med.unc.edu.|School of Medicine, University of North Carolina at Chapel Hill, 6211 Marsico Hall, Chapel Hill, North Carolina, 27599-7290, USA. miriam_braunstein@med.unc.edu.
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Braunstein
authors.affiliation: RTI International, 3040 Cornwallis Road, Research Triangle Park, North Carolina, 27709, USA. ahickey@rti.org.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hickey
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage*; D004952:Esters; D006168:Guinea Pigs; D008297:Male; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000502:physiology; D011718:Pyrazinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy / Q000378:metabolism; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000336:Aerosols; D000995:Antitubercular Agents; D004952:Esters; D011718:Pyrazinamide; C005296:pyrazinoic acid
keywords: TB drugs; inhaled therapy; pyrazinoic acid; pyrazinoic acid esters; tuberculosis