Efficacious In Vitro and In Vivo Effects of Dihydrosphingosine-Ethambutol Analogues Against Susceptible and Multi-drug-resistant Mycobacterium tuberculosis

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• 作者：Esther del Olmo^a ; ^&lowast ; ; Gloria M. Molina-Salinas^b ; Estela I. Bini^c ; Silvia Gonzá ; lez-Herná ; ndez^b ; Luis A. Bustos^a ; Ricardo Escarcena^a ; Brenda Marquina-Castillo^c ; Dulce Mata-Espinosa^c ; Jorge Barrios-Payá ; n^c ; Diego Gonzá ; lez-Ramí ; rez^b ; ^&dagger ; ; Salvador Said Ferná ; ndez^b ; ^&lowast ; ; Arturo San Feliciano^a ; ^&lowast ; ; Rogelio Herná ; ndez-Pando^c ; ^&lowast ; ; ^{rhdezpando@hotmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Tuberculosis ; MDR Mycobacterium tuberculosis ; Dihydrosphingosine analogues ; Ethambutol ; Murine model ; In vitro evaluation
• 刊名：Archives of Medical Research
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：47
• 期：4
• 页码：262-270
• 全文大小：730 K

文摘

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.

Methods

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.

Results

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).

Conclusions

Compound 2b can be considered as a new drug candidate to continue its development against M. tuberculosis MDR strains.