Chloroquine as a potential adjunctive therapy in tuberculosis (original) (raw)

European Respiratory Journal, 2014

Abstract

The rise of multi-drug resistant tuberculosis is a major threat. Multi drug efflux pumps are believed to significantly contribute to the development of resistance by reducing the intracellular concentration of the standard therapy, consisting of isoniazid (INH), ethambutol (ETH), rifampicin (RIF) and pyrazinamid (PZA). Immunohistochemical staining from a patient with tuberculosis of the lymphnodes revealed significant expression of P-gp and BCRP in macrophages at the site of infection. Next, we screened the interaction of tuberculostatics with P-glycoprotein (P-gp, ABCB1) and Breast Cancer Resistance Protein-1 (BCRP, ABCG2) over-expressed in plasma membranes using an ATPase activity assay. INH and PZA were found to be substrates for BCRP, substantially increasing its activity at clinical concentrations. Moreover, the antimalarial chloroquine inhibited both pumps at clinically relevant concentrations. Differentiated THP-1macropaghes were shown to significantly increase the expression of the respective pumps upon stimulation with interferon (IFN)-γ. In a functional assay, the efflux of INH was reduced in the presence of therapeutic concentrations of chloroquine, as measured in the supernatant with liquid chromatography–high resolution mass spectrometry. This effect was clearly more pronounced in IFN-γ stimulated macrophages. In conclusion, we showed for the first time that INH and PZA are substrates for BCRP. IFN-γ stimulated cells pumped INH out into the extracellular space, an effect which could be reversed by chloroquine. Altogether chloroquine, a safe and well-tolerated drug with a long half-life could enhance intracellular tuberculostatic activity, potentially shortening treatment duration.

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