title: Loperamide Restricts Intracellular Growth of Mycobacterium tuberculosis in Lung Macrophages.
abstract: New approaches for improving tuberculosis (TB) control using adjunct host-directed cellular and repurposed drug therapies are needed. Autophagy plays a crucial role in the response to TB, and a variety of autophagy-inducing drugs that are currently available for various medical conditions may serve as an adjunct treatment in pulmonary TB. Here, we evaluated the potential of loperamide, carbamazepine, valproic acid, verapamil, and rapamycin to enhance the antimicrobial immune response to Mycobacterium tuberculosis (Mtb). Human monocyte-derived macrophages (MDMs) and murine alveolar cells (MACs) were infected with Mtb and treated with loperamide, carbamazepine, valproic acid, verapamil, and rapamycin in vitro. Balb/c mice were intraperitoneally administered loperamide, valproic acid, and verapamil, and MACs were infected in vitro with Mtb. The induction of autophagy, the containment of Mtb within autophagosomes and the intracellular Mtb burden were determined. Autophagy was induced by all of the drugs in human and mouse macrophages, and loperamide significantly increased the colocalization of microtubule-associated protein 1 light chain 3 with Mtb in MDMs. Carbamazepine, loperamide, and valproic acid induced microtubule-associated protein 1 light chain 3 and autophagy related 16- like protein 1 gene expression in MDMs and in MACs. Loperamide also induced a reduction in TNF-α production. Loperamide and verapamil induced autophagy, which was associated with a significant reduction in the intracellular growth of Mtb in MACs and alveolar macrophages. The intraperitoneal administration of loperamide and valproic acid induced autophagy in freshly isolated MACs. The antimycobacterial activity in MACs was higher after loperamide treatment and was associated with the degradation of p62. In conclusion, loperamide shows potential as an adjunctive therapy for the treatment of TB.
authors.affiliation: 1 Department of Microbiology and.
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Juárez
authors.affiliation: 1 Department of Microbiology and.
authors.forename: Claudia
authors.initials: C
authors.lastname: Carranza
authors.affiliation: 1 Department of Microbiology and.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Sánchez
authors.affiliation: 1 Department of Microbiology and.
authors.forename: Mitzi
authors.initials: M
authors.lastname: González
authors.affiliation: 2 Department of Bronchial Hyperreactivity, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
authors.forename: Jaime
authors.initials: J
authors.lastname: Chávez
authors.affiliation: 1 Department of Microbiology and.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sarabia
authors.affiliation: 1 Department of Microbiology and.
authors.forename: Martha
authors.initials: M
authors.lastname: Torres
authors.affiliation: 1 Department of Microbiology and.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sada
mesh_terms: D000818:Animals; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D002220:Carbamazepine / Q000494:pharmacology; D006801:Humans; D042541:Intracellular Space / Q000382:microbiology*; D008139:Loperamide / Q000494:pharmacology*; D008168:Lung / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology* / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology; D014774:Virulence / Q000187:drug effects
chemical_list: D002220:Carbamazepine; D014635:Valproic Acid; D008139:Loperamide
keywords: adjunctive therapy for tuberculosis; alveolar macrophages; autophagy; loperamide