Efficacy of pyrazinoic acid dry powder aerosols in resolving necrotic and non-necrotic granulomas in a guinea pig model of tuberculosis

• Published in: PloS one 2018-09, Vol.13 (9), p.e0204495
• Main Authors: Montgomery, Stephanie A, Young, Ellen F, Durham, Phillip G, Zulauf, Katelyn E, Rank, Laura, Miller, Brittany K, Hayden, Jennifer D, Lin, Feng-Chang, Welch, John T, Hickey, Anthony J, Braunstein, Miriam
• Format: Article
• Language: English
• Subjects: Acids; Aerosols; Animals; Antitubercular Agents - administration & dosage; Antitubercular Agents - pharmacokinetics; Bacilli; Bacterial Load; Biology and Life Sciences; Chemotherapy; Critical components; Development and progression; Disease Models, Animal; Dosage and administration; Drug delivery systems; Drug dosages; Drug resistance; Drug therapy; Drug Therapy, Combination; Dry Powder Inhalers; Granuloma, Respiratory Tract - drug therapy; Granuloma, Respiratory Tract - microbiology; Granuloma, Respiratory Tract - pathology; Granulomas; Guinea Pigs; Health aspects; Immunology; Infections; Liver; Lungs; Male; Medicine; Medicine and Health Sciences; Mycobacterium tuberculosis - drug effects; Necrosis; Physical Sciences; Powder; Pyrazinamide; Pyrazinamide - administration & dosage; Pyrazinamide - analogs & derivatives; Pyrazinamide - pharmacokinetics; Research and Analysis Methods; Respiratory Tract Absorption; Rifampin; Rifampin - administration & dosage; Spleen; Sterilization; Testing; Therapy; Tuberculosis; Tuberculosis, Multidrug-Resistant - drug therapy; Tuberculosis, Multidrug-Resistant - pathology; Tuberculosis, Pulmonary - drug therapy; Tuberculosis, Pulmonary - microbiology; Tuberculosis, Pulmonary - pathology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0204495

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.