title: Mefloquine and its oxazolidine derivative compound are active against drug-resistant Mycobacterium tuberculosis strains and in a murine model of tuberculosis infection.
abstract: Repurposing of drugs to treat tuberculosis (TB) has been considered an alternative to overcome the global TB epidemic, especially to combat drug-resistant forms of the disease. Mefloquine has been reported as a potent drug to kill drug-resistant strains of Mycobacterium tuberculosis. In addition, mefloquine-derived molecules have been synthesised and their effectiveness against mycobacteria has been assessed. In this work, we demonstrate for the first time the activities of mefloquine and its oxazolidine derivative compound 1E in a murine model of TB infection following administration of both drugs by the oral route. The effects of associations between mefloquine or 1E with the clinically used antituberculosis drugs isoniazid, rifampicin, ethambutol, moxifloxacin and streptomycin were also investigated. Importantly, combination of mefloquine with isoniazid and of 1E with streptomycin showed a two-fold decrease in their minimum inhibitory concentrations (MICs). Moreover, no tested combinations demonstrated antagonist interactions. Here we describe novel evidence on the activity of mefloquine and 1E against a series of quinolone-resistant M. tuberculosis strains. These data show MICs against quinolone-resistant strains (0.5-8 µg/mL) similar to or lower than those previously reported for multidrug-resistant strains. Taking these results together, we can suggest the use of mefloquine or 1E in combination with clinically available drugs, especially in the case of resistant forms of TB.
authors.affiliation: Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF) and Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga 6681 - Prédio 92A Tecnopuc, 90619-900 Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Medicina e Ciências da Saúde, PUCRS, Porto Alegre, Brazil; Instituto de Toxicologia e Farmacologia, PUCRS, Porto Alegre, Brazil.
authors.forename: Valnês S
authors.initials: VS
authors.lastname: Rodrigues-Junior
authors.affiliation: Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF) and Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga 6681 - Prédio 92A Tecnopuc, 90619-900 Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Medicina e Ciências da Saúde, PUCRS, Porto Alegre, Brazil.
authors.forename: Anne D
authors.initials: AD
authors.lastname: Villela
authors.affiliation: Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Raoni S B
authors.initials: RS
authors.lastname: Gonçalves
authors.affiliation: Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF) and Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga 6681 - Prédio 92A Tecnopuc, 90619-900 Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Biologia Celular e Molecular, PUCRS, Porto Alegre, Brazil.
authors.forename: Bruno Lopes
authors.initials: BL
authors.lastname: Abbadi
authors.affiliation: Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF) and Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga 6681 - Prédio 92A Tecnopuc, 90619-900 Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Biologia Celular e Molecular, PUCRS, Porto Alegre, Brazil.
authors.forename: Rogério Valim
authors.initials: RV
authors.lastname: Trindade
authors.affiliation: Servei de Microbiologia, CDB, Hospital Clínic de Barcelona-ISGlobal, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Alexandre
authors.initials: A
authors.lastname: López-Gavín
authors.affiliation: Servei de Microbiologia, CDB, Hospital Clínic de Barcelona-ISGlobal, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Griselda
authors.initials: G
authors.lastname: Tudó
authors.affiliation: Servei de Microbiologia, CDB, Hospital Clínic de Barcelona-ISGlobal, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Julian
authors.initials: J
authors.lastname: González-Martín
authors.affiliation: Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF) and Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga 6681 - Prédio 92A Tecnopuc, 90619-900 Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Medicina e Ciências da Saúde, PUCRS, Porto Alegre, Brazil; Programa de Pós-Graduação em Biologia Celular e Molecular, PUCRS, Porto Alegre, Brazil.
authors.forename: Luiz Augusto
authors.initials: LA
authors.lastname: Basso
authors.affiliation: Fundação Oswaldo Cruz, Instituto de Tecnologia de Fármacos (Farmanguinhos), Rio de Janeiro, Brazil; Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Marcus V N
authors.initials: MV
authors.lastname: de Souza
authors.affiliation: Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF) and Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga 6681 - Prédio 92A Tecnopuc, 90619-900 Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Medicina e Ciências da Saúde, PUCRS, Porto Alegre, Brazil; Instituto de Toxicologia e Farmacologia, PUCRS, Porto Alegre, Brazil; Faculdade de Odontologia, PUCRS, Porto Alegre, Brazil.
authors.forename: Maria Martha
authors.initials: MM
authors.lastname: Campos
authors.affiliation: Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF) and Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga 6681 - Prédio 92A Tecnopuc, 90619-900 Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Biologia Celular e Molecular, PUCRS, Porto Alegre, Brazil. Electronic address: diogenes@pucrs.br.
authors.forename: Diógenes Santiago
authors.initials: DS
authors.lastname: Santos
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D058491:Bacterial Load; D004195:Disease Models, Animal; D004347:Drug Interactions; D058492:Drug Repositioning; D008297:Male; D015767:Mefloquine / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D010080:Oxazoles; C064210:oxazolidine; D015767:Mefloquine
keywords: Combination; Mefloquine; Murine model; Quinolone-resistant strains; Tuberculosis