title: Therapeutic efficacy of liposomes containing 4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine in a murine model of progressive pulmonary tuberculosis.
abstract: OBJECTIVE
  Tuberculosis (TB) is one of the deadliest infectious diseases and comprises a global public health concern because co-infection with Human immunodeficiency virus (HIV) and, in particular, the continuous isolation of new Multidrug-resistant strains (MDR), rendering the discovery of novel anti-TB agents a strategic priority. One of the most effective first-line mycobactericidal drugs is Isoniazid (INH). Previously, we reported in vitro anti-mycobacterial activity against sensitive and MDR Mycobacterium tuberculosis strains of a new oxadiazole obtained from the hybridization of INH and palmitic acid. The present study evaluated the therapeutic potential of liposomes including Phosphatidylcholine (PC) and L-α Phosphatidic acid (PA) or PC and Cholesterol (Chol) containing 4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine in BALB/c male mice infected by intratracheal (i.t.) route with drug-sensitive or MDR M. tuberculosis.
  
  
  METHODS
  The lipophilic 4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine was obtained to mix INH and palmitoyl chloride. The in vivo anti-TB effect of this oxadiazole derivative contained in two different liposomes was tested in BALB/c mice infected with a sensitive strain of M. tuberculosis, initiating treatment 2 months post-infection, by i.t. route, of 50 μg of oxadiazole derivative for 1 month. In a second stage, mice were infected with an MDR (resistant to first-line drugs) and treated with 150 μg of an oxadiazole derivative carried by PC + Chol liposomes for 2 months. The effect of the oxadiazole derivative in vivo was determined by the quantification of lung bacilli loads and histopathology.
  
  
  RESULTS
  In comparison with control animals, drug-sensitive, strain-infected mice treated for 1 month with 50 μg of this oxadiazole derivative contained in the liposomes of PC + Chol showed a significant, 80% decrease of live bacilli in lungs, which correlated with the morphometric observation, and the group of MDR clinical isolate-infected mice treated with 150 μg of the oxadiazole derivative contained in the same type of liposome showed significantly lower lung bacillary loads than control mice, producing 90% of bacilli burden reduction after 2 months of treatment.
  
  
  CONCLUSIONS
  These results confirm and extend the reported highly efficient anti-mycobacterial activity of this lipophilic oxidazole derivative when it is carried by liposomes in mice suffering from late progressive pulmonary TB induced by drug-sensitive, and most prominently by, MDR strains.
authors.affiliation: Sección de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Col. Vasco de Quiroga No. 15, Delegación Tlalpan, 14080 México, D.F., Mexico. Electronic address: dulmat@yahoo.com.mx.
authors.forename: Dulce
authors.initials: D
authors.lastname: Mata-Espinosa
authors.affiliation: Unidad de Investigación Médica Yucatán, Unidad Médica de Alta Especialidad (UMAE), Centro Médico Nacional Lic. Ignacio García Téllez, Instituto Mexicano del Seguro Social (IMSS), Calle 41 No. 439, x 32 y 34, Col. Industrial, 97150 Mérida, Yucatán, Mexico. Electronic address: gmolina70@gmail.com.
authors.forename: Gloria María
authors.initials: GM
authors.lastname: Molina-Salinas
authors.affiliation: Sección de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Col. Vasco de Quiroga No. 15, Delegación Tlalpan, 14080 México, D.F., Mexico. Electronic address: qcjbp77@yahoo.com.mx.
authors.forename: Jorge
authors.initials: J
authors.lastname: Barrios-Payán
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos (UAEM), Av. Universidad No. 1001, Col. Chamilpa, 62209 Cuernavaca, Morelos, Mexico. Electronic address: gabriel_navarrete@uaem.mx.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Navarrete-Vázquez
authors.affiliation: Sección de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Col. Vasco de Quiroga No. 15, Delegación Tlalpan, 14080 México, D.F., Mexico. Electronic address: brenda.marquina@gmail.com.
authors.forename: Brenda
authors.initials: B
authors.lastname: Marquina
authors.affiliation: Sección de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Col. Vasco de Quiroga No. 15, Delegación Tlalpan, 14080 México, D.F., Mexico. Electronic address: octavioramos13@gmail.com.
authors.forename: Octavio
authors.initials: O
authors.lastname: Ramos-Espinosa
authors.affiliation: Sección de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Col. Vasco de Quiroga No. 15, Delegación Tlalpan, 14080 México, D.F., Mexico. Electronic address: estelabini@yahoo.com.ar.
authors.forename: Estela Isabel
authors.initials: EI
authors.lastname: Bini
authors.affiliation: Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional (INP), Prolongación de Carpio y Plan de Ayala S/N, Col. Santo Tomás, Delegación Miguel Hidalgo, 11349 México, D.F., Mexico. Electronic address: isabelbaeza@yahoo.com.
authors.forename: Isabel
authors.initials: I
authors.lastname: Baeza
authors.affiliation: Sección de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Col. Vasco de Quiroga No. 15, Delegación Tlalpan, 14080 México, D.F., Mexico. Electronic address: rhdezpando@hotmail.com.
authors.forename: Rogelio
authors.initials: R
authors.lastname: Hernández-Pando
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002784:Cholesterol / Q000737:chemistry; D004195:Disease Models, Animal; D007538:Isoniazid / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification*; D010069:Oxadiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D010712:Phosphatidic Acids / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
chemical_list: C000605879:4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine; D000995:Antitubercular Agents; D008081:Liposomes; D010069:Oxadiazoles; D010712:Phosphatidic Acids; D010713:Phosphatidylcholines; D011725:Pyridines; D002784:Cholesterol; D007538:Isoniazid
keywords: 1,3,4-Oxadiazol,4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine; Lipophilic; Liposomes; MDR; Mycobacterium tuberculosis