De Groote Mary A, Jarvis Thale C, Wong Christina, Graham James, Hoang Teresa, Young Casey L, Ribble Wendy, Day Joshua, Li Wei, Jackson Mary, Gonzalez-Juarrero Mercedes, Sun Xicheng, Ochsner Urs A
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States.
Crestone, Inc., Boulder, CO, United States.
Front Microbiol. 2018 Sep 20;9:2231. doi: 10.3389/fmicb.2018.02231. eCollection 2018.
Mycobacteria remain an important problem worldwide, especially drug resistant human pathogens. Novel therapeutics are urgently needed to tackle both drug-resistant tuberculosis (TB) and difficult-to-treat infections with nontuberculous mycobacteria (NTM). Benzothiazole adamantyl amide had previously emerged as a high throughput screening hit against () and was subsequently found to be active against NTM as well. For lead optimization, we applied an iterative process of design, synthesis and screening of several 100 analogs to improve antibacterial potency as well as physicochemical and pharmacological properties to ultimately achieve efficacy. Replacement of the adamantyl group with cyclohexyl derivatives, including bicyclic moieties, resulted in advanced lead compounds that showed excellent potency and a mycobacteria-specific spectrum of activity. MIC values ranged from 0.03 to 0.12 μg/mL against () and other rapid- growing NTM, 1-2 μg/mL against complex (MAC), and 0.12-0.5 μg/mL against . No pre-existing resistance was found in a collection of = 54 clinical isolates of rapid-growing NTM. Unlike many antibacterial agents commonly used to treat mycobacterial infections, benzothiazole amides demonstrated bactericidal effects against both and . Metabolic labeling provided evidence that the compounds affect the transfer of mycolic acids to their cell envelope acceptors in mycobacteria. Mapping of resistance mutations pointed to the trehalose monomycolate transporter (MmpL3) as the most likely target. efficacy and tolerability of a benzothiazole amide was demonstrated in a mouse model of chronic NTM lung infection with . Once daily dosing over 4 weeks by intrapulmonary microspray administration as 5% corn oil/saline emulsion achieved statistically significant CFU reductions compared to vehicle control and non-inferiority compared to azithromycin. The benzothiazole amides hold promise for development of a novel therapeutic agent with broad antimycobacterial activity, though further work is needed to develop drug formulations for direct intrapulmonary delivery via aerosol.
分枝杆菌在全球范围内仍然是一个重要问题，尤其是耐药性人类病原体。迫切需要新型疗法来应对耐药性结核病（TB）以及非结核分枝杆菌（NTM）引起的难治性感染。苯并噻唑金刚烷基酰胺先前已作为针对（）的高通量筛选命中物出现，随后发现它对NTM也有活性。为了进行先导化合物优化，我们应用了一个迭代过程，对数百种类似物进行设计、合成和筛选，以提高抗菌效力以及物理化学和药理学性质，最终实现疗效。用环己基衍生物（包括双环部分）取代金刚烷基，得到了具有优异效力和分枝杆菌特异性活性谱的先进先导化合物。针对（）和其他快速生长的NTM，其最低抑菌浓度（MIC）值范围为0.03至0.12μg/mL，针对鸟分枝杆菌复合群（MAC）为1 - 2μg/mL，针对（）为0.12至0.5μg/mL。在54株快速生长的NTM临床分离株中未发现预先存在的耐药性。与许多常用于治疗分枝杆菌感染的抗菌剂不同，苯并噻唑酰胺对（）和（）均表现出杀菌作用。代谢标记提供了证据，表明这些化合物会影响分枝杆菌中分枝菌酸向其细胞壁受体的转移。耐药突变图谱表明海藻糖单分枝菌酸转运蛋白（MmpL3）是最可能的靶点。在慢性NTM肺部感染的小鼠模型中证明了一种苯并噻唑酰胺的疗效和耐受性。与赋形剂对照相比，通过肺内微喷雾给药作为5%玉米油/盐水乳液，每日一次给药4周，实现了统计学上显著的菌落形成单位（CFU）减少，与阿奇霉素相比不劣于后者。苯并噻唑酰胺有望开发出一种具有广泛抗分枝杆菌活性的新型治疗剂，不过还需要进一步开展工作来开发通过气雾剂直接肺内给药的药物制剂。
