The prevalence of pulmonary infections due to nontuberculous mycobacteria such as Mycobacterium abscessus has been increasing and surpassing tuberculosis (TB) in some industrialized countries. Because of intrinsic resistance to most antibiotics that drastically limits conventional chemotherapeutic treatment options, new anti-M. abscessus therapeutics are urgently needed against this emerging pathogen. Extensive screening of a library of benzimidazole derivatives that were previously shown to be active against Mycobacterium tuberculosis led to the identification of a lead compound exhibiting very potent in vitro activity against a wide panel of M. abscessus clinical strains. Designated EJMCh-6, this compound, a 2-(2-cyclohexylethyl)-5,6-dimethyl-1H-benzo[d]imidazole), also exerted very strong activity against intramacrophage-residing M. abscessus. Moreover, the treatment of infected zebrafish embryos with EJMCh-6 was correlated with significantly increased embryo survival and a decrease in the bacterial burden as compared to those for untreated fish. Insights into the mechanism of action were inferred from the generation of spontaneous benzimidazole-resistant strains and the identification of a large set of missense mutations in MmpL3, the mycolic acid transporter in mycobacteria. Overexpression of the mutated mmpL3 alleles in a susceptible M. abscessus strain was associated with high resistance levels to EJMCh-6 and to other known MmpL3 inhibitors. Mapping the mutations conferring resistance on an MmpL3 three-dimensional homology model defined a potential EJMCh-6-binding cavity. These data emphasize a yet unexploited chemical structure class against M. abscessus with promising translational development for the treatment of M. abscessus lung diseases.

中文翻译：

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靶向脓肿分枝杆菌中MmpL3转运蛋白的活性苯并咪唑衍生物。

在一些工业化国家中，由非结核性分枝杆菌（如脓肿分枝杆菌）引起的肺部感染的流行率正在上升，并超过了结核病。由于对大多数抗生素的固有抗性极大地限制了常规化学疗法的治疗选择，因此新的抗-M。迫切需要针对这种新兴病原体的脓肿疗法。苯并咪唑衍生物的文库的广泛筛选，以前显示其对结核分枝杆菌具有活性，导致鉴定了对多种脓毒症临床菌株表现出非常有效的体外活性的先导化合物。指定为EJMCh-6的该化合物2-（2-环己基乙基）-5,6-二甲基-1H-苯并[d]咪唑）对巨噬细胞内的脓肿支原体也具有非常强的活性。此外，与未处理的鱼相比，用EJMCh-6处理受感染的斑马鱼胚胎与胚胎存活率显着提高和细菌负担减少有关。从自发的苯并咪唑抗性菌株的产生以及对MmpL3（分枝杆菌中的分枝酸转运蛋白）的大量错义突变的鉴定，可以推断出其作用机理。易感性脓肿菌株中mmpL3等位基因突变的过度表达与对EJMCh-6和其他已知MmpL3抑制剂的高抗性水平相关。在MmpL3三维同源模型上绘制赋​​予抗性的突变，从而确定了潜在的EJMCh-6结合腔。这些数据强调了针对M的尚未利用的化学结构分类。