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Efficacy of pyrazinoic acid dry powder aerosols in resolving necrotic and non-necrotic granulomas in a guinea pig model of tuberculosis.
PLoS One. 2018; 13(9):e0204495.Plos

Abstract

New therapeutic strategies are needed to treat drug resistant tuberculosis (TB) and to improve treatment for drug sensitive TB. Pyrazinamide (PZA) is a critical component of current first-line TB therapy. However, the rise in PZA-resistant TB cases jeopardizes the future utility of PZA. To address this problem, we used the guinea pig model of TB and tested the efficacy of an inhaled dry powder combination, referred to as Pyrazinoic acid/ester Dry Powder (PDP), which is comprised of pyrazinoic acid (POA), the active moiety of PZA, and pyrazinoic acid ester (PAE), which is a PZA analog. Both POA and PAE have the advantage of being able to act on PZA-resistant Mycobacterium tuberculosis. When used in combination with oral rifampicin (R), inhaled PDP had striking effects on tissue pathology. Effects were observed in lungs, the site of delivery, but also in the spleen and liver indicating both local and systemic effects of inhaled PDP. Tissue granulomas that harbor M. tuberculosis in a persistent state are a hallmark of TB and they pose a challenge for therapy. Compared to other treatments, which preferentially cleared non-necrotic granulomas, R+PDP reduced necrotic granulomas more effectively. The increased ability of R+PDP to act on more recalcitrant necrotic granulomas suggests a novel mechanism of action. The results presented in this report reveal the potential for developing therapies involving POA that are optimized to target necrotic as well as non-necrotic granulomas as a means of achieving more complete sterilization of M. tuberculosis bacilli and preventing disease relapse when therapy ends.

Authors+Show Affiliations

Department of Pathology and Laboratory Medicine and Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.RTI International, Research Triangle Park, North Carolina, United States of America.Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.Department of Biostatistics and North Carolina Translational and Clinical Sciences Institute, University of North Carolina, Chapel Hill, North Carolina, United States of America.Department of Chemistry, University at Albany, Albany, New York, United States of America.RTI International, Research Triangle Park, North Carolina, United States of America.Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

30261007

Citation

Montgomery, Stephanie A., et al. "Efficacy of Pyrazinoic Acid Dry Powder Aerosols in Resolving Necrotic and Non-necrotic Granulomas in a Guinea Pig Model of Tuberculosis." PloS One, vol. 13, no. 9, 2018, pp. e0204495.
Montgomery SA, Young EF, Durham PG, et al. Efficacy of pyrazinoic acid dry powder aerosols in resolving necrotic and non-necrotic granulomas in a guinea pig model of tuberculosis. PLoS ONE. 2018;13(9):e0204495.
Montgomery, S. A., Young, E. F., Durham, P. G., Zulauf, K. E., Rank, L., Miller, B. K., Hayden, J. D., Lin, F. C., Welch, J. T., Hickey, A. J., & Braunstein, M. (2018). Efficacy of pyrazinoic acid dry powder aerosols in resolving necrotic and non-necrotic granulomas in a guinea pig model of tuberculosis. PloS One, 13(9), e0204495. https://doi.org/10.1371/journal.pone.0204495
Montgomery SA, et al. Efficacy of Pyrazinoic Acid Dry Powder Aerosols in Resolving Necrotic and Non-necrotic Granulomas in a Guinea Pig Model of Tuberculosis. PLoS ONE. 2018;13(9):e0204495. PubMed PMID: 30261007.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Efficacy of pyrazinoic acid dry powder aerosols in resolving necrotic and non-necrotic granulomas in a guinea pig model of tuberculosis. AU - Montgomery,Stephanie A, AU - Young,Ellen F, AU - Durham,Phillip G, AU - Zulauf,Katelyn E, AU - Rank,Laura, AU - Miller,Brittany K, AU - Hayden,Jennifer D, AU - Lin,Feng-Chang, AU - Welch,John T, AU - Hickey,Anthony J, AU - Braunstein,Miriam, Y1 - 2018/09/27/ PY - 2018/01/12/received PY - 2018/09/10/accepted PY - 2018/9/28/entrez PY - 2018/9/28/pubmed PY - 2019/3/16/medline SP - e0204495 EP - e0204495 JF - PloS one JO - PLoS ONE VL - 13 IS - 9 N2 - New therapeutic strategies are needed to treat drug resistant tuberculosis (TB) and to improve treatment for drug sensitive TB. Pyrazinamide (PZA) is a critical component of current first-line TB therapy. However, the rise in PZA-resistant TB cases jeopardizes the future utility of PZA. To address this problem, we used the guinea pig model of TB and tested the efficacy of an inhaled dry powder combination, referred to as Pyrazinoic acid/ester Dry Powder (PDP), which is comprised of pyrazinoic acid (POA), the active moiety of PZA, and pyrazinoic acid ester (PAE), which is a PZA analog. Both POA and PAE have the advantage of being able to act on PZA-resistant Mycobacterium tuberculosis. When used in combination with oral rifampicin (R), inhaled PDP had striking effects on tissue pathology. Effects were observed in lungs, the site of delivery, but also in the spleen and liver indicating both local and systemic effects of inhaled PDP. Tissue granulomas that harbor M. tuberculosis in a persistent state are a hallmark of TB and they pose a challenge for therapy. Compared to other treatments, which preferentially cleared non-necrotic granulomas, R+PDP reduced necrotic granulomas more effectively. The increased ability of R+PDP to act on more recalcitrant necrotic granulomas suggests a novel mechanism of action. The results presented in this report reveal the potential for developing therapies involving POA that are optimized to target necrotic as well as non-necrotic granulomas as a means of achieving more complete sterilization of M. tuberculosis bacilli and preventing disease relapse when therapy ends. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/30261007/Efficacy_of_pyrazinoic_acid_dry_powder_aerosols_in_resolving_necrotic_and_non_necrotic_granulomas_in_a_guinea_pig_model_of_tuberculosis_ L2 - http://dx.plos.org/10.1371/journal.pone.0204495 DB - PRIME DP - Unbound Medicine ER -