Efficacious In Vitro and In Vivo Effects of Dihydrosphingosine-Ethambutol Analogues Against Susceptible and Multi-drug-resistant Mycobacterium tuberculosis.
Tuberculosis (TB) is a major worldwide health problem in part due to the lack of new drugs and the emergence of multidrug-resistant strains (MDR). The aim of this study was to select anti-tuberculosis drug candidates from a collection of 69 synthetic sphingosine-ethambutol analogues through in vitro and in vivo evaluations.



The 69 compounds were evaluated in vitro against two Mycobacterium tuberculosis strains, a drug susceptible (H37Rv) and a MDR clinical isolate (CIBIN-99). Four selected compounds, those that exhibited the highest potency in vitro, were tested in vivo using a model of progressive TB in BALB/c mice infected with the drug susceptible strain, either alone or combined with conventional chemotherapy, as well as in mice infected with the MDR strain. The acute toxicity was evaluated on male and female adult BALB/c mice.



Ten of the evaluated compounds resulted more potent in vitro than ethambutol. The experimental compound 2b (2-aminopalmitol benzyl ether) was the most efficacious and also showed additive effects in combination with conventional chemotherapy. It did not exhibit toxicity (LD50 >2000 mg/kg).



Compound 2b can be considered as a new drug candidate to continue its development against M. tuberculosis MDR strains.
Departamento de Química Farmacéutica, Facultad de Farmacia, CIETUS, IBSAL, Universidad de Salamanca, Salamanca, Spain.
Esther Del
ED
Olmo
Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social (IMSS), Monterrey, Nuevo León, México.
Gloria M
GM
Molina-Salinas
Sección de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), México City, México.
Estela I
EI
Bini
Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social (IMSS), Monterrey, Nuevo León, México.
Silvia
S
González-Hernández
Departamento de Química Farmacéutica, Facultad de Farmacia, CIETUS, IBSAL, Universidad de Salamanca, Salamanca, Spain.
Luis A
LA
Bustos
Departamento de Química Farmacéutica, Facultad de Farmacia, CIETUS, IBSAL, Universidad de Salamanca, Salamanca, Spain.
Ricardo
R
Escarcena
Sección de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), México City, México.
Brenda
B
Marquina-Castillo
Sección de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), México City, México.
Dulce
D
Mata-Espinosa
Sección de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), México City, México.
Jorge
J
Barrios-Payán
Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social (IMSS), Monterrey, Nuevo León, México.
Diego
D
González-Ramírez
Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social (IMSS), Monterrey, Nuevo León, México.
Salvador Said
SS
Fernández
Departamento de Química Farmacéutica, Facultad de Farmacia, CIETUS, IBSAL, Universidad de Salamanca, Salamanca, Spain.
Arturo
A
San Feliciano
Sección de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), México City, México. Electronic address: rhdezpando@hotmail.com.
Rogelio
R
Hernández-Pando
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D004977:Ethambutol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000382:microbiology
D000995:Antitubercular Agents; D004977:Ethambutol; D013110:Sphingosine; C005682:safingol
Dihydrosphingosine analogues; Ethambutol; In vitro evaluation; MDR Mycobacterium tuberculosis; Murine model; Tuberculosis