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Abstract：
Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which shows anti-tuberculosis and non-tuberculous mycobacteria (NTM) activities but, unlike BDQ, did not prolong QT interval in animal model studies. This study evaluated the antibacterial activity of this novel compound against Mycobacterium avium, Mycobacterium abscessus, and Mycobacterium chelonae in vitro and in vivo. The minimum inhibitory concentration (MIC) of WX-081 against three kinds of non-tuberculous mycobacteria (NTM) clinical strains was determined using microplate-based alamarBlue assay (MABA), and the antibacterial activity of WX-081 against NTM in J774A.1 cells and mice was evaluated. MIC ranges of WX-081 against clinical strains of M. avium and M. abscessus were 0.05-0.94 μg/mL, 0.88-7.22 μg/mL (M. abscessus subsp. abscessus), and 0.22-8.67 μg/mL (M. abscessus subsp. massiliense), respectively, which were slightly higher than those of BDQ. For M. avium, M. abscessus, and M. chelonae, WX-081 can reduce the intracellular bacterial load by 0.13-1.18, 0.18-1.50, and 0.17-1.03 log10 colony forming units (CFU)/mL, respectively, in a concentration-dependent manner. WX-081 has bactericidal activity against three NTM species in mice. WX-081 exhibited anti-NTM activity to the same extent as BDQ both in vivo and in vitro. WX-081 is a promising clinical candidate and should be studied further in clinical trials.
OBJECTIVE: Due to the rapidly increased cases globally, non-tuberculous mycobacteria (NTM) disease has become a significant public health problem. NTM accounted for 11.57% of all mycobacterial isolates in China, with a high detection rate of Mycobacterium abscessus, Mycobacterium avium, and Mycobacterium chelonae during 2000-2019. Treatment of NTM infection is often challenging, as natural resistance to most antibiotics is quite common among different NTM species. Hence, identifying highly active anti-NTM agents is a priority for potent regimen establishment. The pursuit of new drugs to treat multidrug-resistant tuberculosis may also identify some agents with strong activity against NTM. Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which was developed to retain the anti-tuberculosis efficacy but eliminates the severe side effects of BDQ. This study initially evaluated the antimicrobial activity of this novel compound against M. avium, M. abscessus, and M. chelonae in vitro, in macrophages and mice, respectively.
OBJECTIVE: Due to the rapidly increased cases globally, non-tuberculous mycobacteria (NTM) disease has become a significant public health problem. NTM accounted for 11.57% of all mycobacterial isolates in China, with a high detection rate of Mycobacterium abscessus, Mycobacterium avium, and Mycobacterium chelonae during 2000-2019. Treatment of NTM infection is often challenging, as natural resistance to most antibiotics is quite common among different NTM species. Hence, identifying highly active anti-NTM agents is a priority for potent regimen establishment. The pursuit of new drugs to treat multidrug-resistant tuberculosis may also identify some agents with strong activity against NTM. Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which was developed to retain the anti-tuberculosis efficacy but eliminates the severe side effects of BDQ. This study initially evaluated the antimicrobial activity of this novel compound against M. avium, M. abscessus, and M. chelonae in vitro, in macrophages and mice, respectively.
摘要：
Sudapyridine（WX-081）是贝达奎林（BDQ）的结构类似物，显示抗结核和非结核分枝杆菌(NTM)活性，但是，不像BDQ,在动物模型研究中没有延长QT间期。这项研究评估了这种新型化合物对鸟分枝杆菌的抗菌活性，脓肿分枝杆菌,和活体外分枝杆菌。使用基于微孔板的alamarBlue测定法（MABA）确定WX-081对三种非结核分枝杆菌（NTM）临床菌株的最低抑菌浓度（MIC），并评价了WX-081在J774A.1细胞和小鼠中对NTM的抗菌活性。WX-081对鸟分枝杆菌和脓肿分枝杆菌临床菌株的MIC范围为0.05-0.94μg/mL，0.88-7.22μg/mL(M.脓肿亚科。脓肿)，和0.22-8.67μg/mL(M.脓肿亚科。massiliense)，分别,略高于BDQ。对于M.avium,M.脓肿，和M.chelonae，WX-081可将细胞内细菌负荷降低0.13-1.18、0.18-1.50和0.17-1.03log10菌落形成单位（CFU）/mL，分别,以浓度依赖的方式。WX-081对小鼠中的三种NTM物种具有杀菌活性。WX-081在体内和体外表现出与BDQ相同程度的抗NTM活性。WX-081是一种有前途的临床候选药物，应在临床试验中进一步研究。重要性由于全球病例迅速增加，非结核分枝杆菌（NTM）疾病已成为重要的公共卫生问题。NTM占中国所有分枝杆菌分离株的11.57%，脓肿分枝杆菌检出率高,鸟分枝杆菌,和龟分枝杆菌在2000-2019年期间。NTM感染的治疗通常具有挑战性，因为对大多数抗生素的天然抗性在不同的NTM物种中相当普遍。因此，鉴定高活性抗NTM药物是建立有效治疗方案的优先事项。对治疗耐多药结核病的新药的追求也可能会发现一些对NTM具有强活性的药物。Sudapyridine（WX-081）是贝达奎林（BDQ）的结构类似物，它的开发是为了保留抗结核功效，但消除了BDQ的严重副作用。这项研究最初评估了这种新型化合物对鸟分枝杆菌的抗菌活性，M.脓肿，和体外培养的龟分枝杆菌，在巨噬细胞和小鼠中，分别。
