Mata-Espinosa Dulce, Molina-Salinas Gloria María, Barrios-Payán Jorge, Navarrete-Vázquez Gabriel, Marquina Brenda, Ramos-Espinosa Octavio, Bini Estela Isabel, Baeza Isabel, Hernández-Pando Rogelio
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.
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.
Pulm Pharmacol Ther. 2015 Jun;32:7-14. doi: 10.1016/j.pupt.2015.03.004. Epub 2015 Apr 2.
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.
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.
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.
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.
结核病是最致命的传染病之一，由于与人类免疫缺陷病毒（HIV）合并感染，尤其是新的多重耐药菌株（MDR）不断出现，已成为全球公共卫生问题，因此发现新型抗结核药物成为战略重点。异烟肼（INH）是最有效的一线杀分枝杆菌药物之一。此前，我们报道了一种通过INH与棕榈酸杂交获得的新型恶二唑对敏感和耐多药结核分枝杆菌菌株的体外抗分枝杆菌活性。本研究评估了含4-(5-十五烷基-1,3,4-恶二唑-2-基)吡啶的磷脂酰胆碱（PC）和L-α磷脂酸（PA）或PC和胆固醇（Chol）脂质体在经气管内（i.t.）途径感染药物敏感或耐多药结核分枝杆菌的BALB/c雄性小鼠中的治疗潜力。
通过将INH与棕榈酰氯混合得到亲脂性的4-(5-十五烷基-1,3,4-恶二唑-2-基)吡啶。在感染结核分枝杆菌敏感菌株的BALB/c小鼠中，于感染后2个月开始通过i.t.途径给予50μg恶二唑衍生物，持续治疗1个月，测试两种不同脂质体中所含该恶二唑衍生物的体内抗结核效果。在第二阶段，小鼠感染耐多药（对一线药物耐药）菌株，并用PC+Chol脂质体携带的150μg恶二唑衍生物治疗2个月。通过定量肺内杆菌负荷和组织病理学来确定恶二唑衍生物的体内效果。
与对照动物相比，用PC+Chol脂质体中所含50μg该恶二唑衍生物治疗1个月的药物敏感菌株感染小鼠，肺内活菌数量显著减少80%，这与形态学观察结果相关；用同一类型脂质体中所含150μg恶二唑衍生物治疗的耐多药临床分离株感染小鼠组，肺内杆菌负荷显著低于对照小鼠，治疗2个月后杆菌负荷降低90%。
这些结果证实并扩展了所报道的这种亲脂性恶二唑衍生物在脂质体携带时对药物敏感尤其是耐多药菌株诱导的晚期进行性肺结核小鼠的高效抗分枝杆菌活性。
