E F Young1, E Perkowski1, S Malik1, J D Hayden1, P G Durham2, L Zhong3, J T Welch3, Miriam S Braunstein4,5, Anthony J Hickey6. 1. Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA. 2. RTI International, 3040 Cornwallis Road, Research Triangle Park, North Carolina, 27709, USA. 3. Department of Chemistry, University of Albany, State University of New York, Albany, New York, 12222, USA. 4. 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. 5. 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. 6. RTI International, 3040 Cornwallis Road, Research Triangle Park, North Carolina, 27709, USA. ahickey@rti.org.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: The present study justifies further evaluation of PZA analogs and their lung delivery to treat TB.
PURPOSE: 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. METHODS: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. RESULTS: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. CONCLUSION: The present study justifies further evaluation of PZA analogs and their lung delivery to treat TB.
Authors: L Garcia-Contreras; Pavan Muttil; John K Fallon; Mohan Kabadi; Robert Gerety; Anthony J Hickey Journal: Antimicrob Agents Chemother Date: 2012-02-13 Impact factor: 5.191
Authors: Lucila Garcia-Contreras; Jean C Sung; Pavan Muttil; Danielle Padilla; Martin Telko; Jarod L Verberkmoes; Katharina J Elbert; Anthony J Hickey; David A Edwards Journal: Antimicrob Agents Chemother Date: 2010-01-19 Impact factor: 5.191
Authors: Phillip G Durham; Shumaila N Hanif; Lucia Garcia Contreras; Ellen F Young; Miriam S Braunstein; Anthony J Hickey Journal: J Vis Exp Date: 2017-03-30 Impact factor: 1.355
Authors: Stephanie A Montgomery; Ellen F Young; Phillip G Durham; Katelyn E Zulauf; Laura Rank; Brittany K Miller; Jennifer D Hayden; Feng-Chang Lin; John T Welch; Anthony J Hickey; Miriam Braunstein Journal: PLoS One Date: 2018-09-27 Impact factor: 3.240