Chloroquine enhances the antimycobacterial activity of isoniazid and pyrazinamide by reversing inflammation-induced macrophage efflux

International Journal of Antimicrobial Agents
U MattJ Nemeth

Abstract

Mycobacterium tuberculosis (MTB) is notorious for persisting within host macrophages. Efflux pumps decrease intracellular drug levels, thus fostering persistence of MTB during therapy. Isoniazid (INH) and pyrazinamide (PZA) are substrates of the efflux pump breast cancer resistance protein-1 (BCRP-1), which is inhibited by chloroquine (CQ). In this study, BCRP-1 was found to be expressed on macrophages of human origin and on foamy giant cells at the site of MTB infection. In the current in vitro study, interferon-gamma (IFNγ) increased the expression of BCRP-1 in macrophages derived from the human monocytic leukaemia cell line THP-1. Using a BCRP-1-specific fluorescent dye and radioactively labelled INH, it was demonstrated that efflux from macrophages increased upon activation with IFNγ. CQ was able to inhibit active efflux and augmented the intracellular concentrations both of INH and the dye. In agreement, CQ and specific inhibition of BCRP-1 increased the antimycobacterial activity of INH against intracellular MTB. Although PZA behaved differently, CQ had comparable advantageous effects on the intracellular pharmacokinetics and activity of PZA. The adjunctive effects of CQ on intracellular killing of MTB were measurable at ...Continue Reading

Citations

Nov 16, 2019·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Michael Dal MolinPeter Sander
Sep 12, 2018·Antimicrobial Agents and Chemotherapy·Ana GomesPaula Gomes
Nov 15, 2019·Science Translational Medicine·Richa MishraAmit Singh
Dec 6, 2020·Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases·Simran KaurGarima Khare
Dec 2, 2020·The International Journal of Biochemistry & Cell Biology·Chae Eun KimSu-Kil Seo
Feb 11, 2021·Immunological Reviews·Gül KilinçMariëlle C Haks
Jul 13, 2021·Frontiers in Immunology·Steven C Mitini-NkhomaHenry C Mwandumba
Jul 21, 2020·ACS Infectious Diseases·Sirle Saul, Shirit Einav
Jan 4, 2018·ACS Infectious Diseases·Stanford Schor, Shirit Einav

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