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Adjunctive host-directed therapy with statins improves tuberculosis-related outcomes in mice

Dutta, NK;Bruiners, N;Zimmerman, MD;Tan, S;Dartois, V;Gennaro, ML;Karakousis, PC;

Tuberculosis (TB) treatment is lengthy and complicated and patients often develop chronic lung disease. Recent attention has focused on host-directed therapies aimed at optimizing immune responses to M. tuberculosis (Mtb), as adjunctive treatment given with anti-tubercular drugs. In addition to their cholesterol-lowering properties, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have broad anti-inflammatory and immunomodulatory activities. In the current study, we screened 8 commercially available statins for cytotoxic effect, anti-tubercular activity, synergy with first-line drugs in macrophages, pharmacokinetics and adjunctive bactericidal activity, and, in two different mouse models, as adjunctive therapy to first-line TB drugs. Pravastatin showed the least toxicity in THP-1 and Vero cells. At non-toxic doses, atorvastatin and mevastatin were unable to inhibit Mtb growth in THP-1 cells. Simvastatin, fluvastatin and pravastatin showed the most favorable therapeutic index, and enhanced the anti-tubercular activity of the first-line drugs isoniazid, rifampin and pyrazinamide in THP-1 cells. Pravastatin modulated phagosomal maturation characteristics in macrophages, phenocopying macrophage activation, and exhibited potent adjunctive activity in the standard mouse model of TB chemotherapy and in a mouse model of human-like necrotic TB lung granulomas. These data provide compelling evidence for clinical evaluation of pravastatin as adjunctive, host-directed therapy for TB. The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  • PubMed ID: 31605489