In this study, we conducted an experimental study to evaluate in vitro susceptibility of Q203 against Mycobacterium tuberculosis, as well as the major pathogenic nontuberculous mycobacterial species. A total of 344 nonduplicate mycobacterium isolates were randomly selected for in vitro susceptibility testing. Overall, Q203 exhibited excellent activity against multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) isolates, whereas it showed high minimum inhibitory concentration (MIC) values for all nontuberculous mycobacteria (NTM) isolates tested. The MIC₅₀ and MIC₉₀ values were both 0.008 mg/L for MDR- and XDR-TB isolates, respectively. In contrast, the MIC₅₀ and MIC₉₀ values of four NTM species were all >16 mg/L. QcrB of M. tuberculosis, a component of the CytBC1 complex of the respiratory chain targeted by Q230, shared 89.7% amino acid sequence identity with Mycobacterium avium QcrB, 87.9% with that of Mycobacterium intracellulare, and 84.0% with that of Mycobacterium fortuitum, whereas with low sequence identity observed in QcrB sequence of Mycobacterium abscessus. Notably, the QcrBs of M. avium and M. intracellulare contained a 10-amino acid insertion in the linker between the eighth and ninth helical region. In conclusion, our data demonstrate the bipolar distribution of Q203 MICs across mycobacterial species. Compared with the high MICs in four clinically relevant mycobacterial species, MDR- and XDR-TB isolates have extremely low MICs, indicating that Q203 is a particularly promising candidate for TB treatment. In addition, the 10-amino acid insertion within QcrBs of M. avium and M. intracellulare may be a plausible explanation for the natural resistance to Q203 among these two species.

中文翻译：

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Q203 最低抑菌浓度在分枝杆菌属中的双极分布

在这项研究中，我们进行了一项实验研究，以评估Q203 对结核分枝杆菌以及主要致病性非结核分枝杆菌物种的体外敏感性。总共随机选择了 344 个非重复的分枝杆菌分离株进行体外药敏试验。总体而言，Q203 对耐多药 (MDR-) 和广泛耐药结核病 (XDR-TB) 分离株表现出优异的活性，而对所有测试的非结核分枝杆菌 (NTM) 分离株显示出较高的最低抑菌浓度 (MIC) 值。MDR-TB 和 XDR-TB 分离株的 MIC ₅₀和 MIC ₉₀值分别为 0.008 mg/L。相比之下，MIC ₅₀四种 NTM 物种的MIC ₉₀和 MIC ₉₀值均 >16 mg/L。的QcrB结核分枝杆菌，该CytBC1复杂通过Q230靶向的呼吸链的一个组成部分，共享89.7％的氨基酸序列同一性鸟分枝杆菌QcrB，87.9％与的胞内分枝杆菌，并与84.0％偶发分枝杆菌，而在脓肿分枝杆菌的QcrB序列中观察到低序列同一性。值得注意的是，的QcrBs鸟分枝杆菌和胞内分枝杆菌在第八个和第九个螺旋区域之间的接头中包含一个 10 个氨基酸的插入。总之，我们的数据证明了 Q203 MIC 在分枝杆菌物种中的双极分布。与四种临床相关分枝杆菌物种的高 MIC 相比，MDR-TB 和 XDR-TB 分离株的 MIC 极低，表明 Q203 是一种特别有前景的 TB 治疗候选物。此外，QcrBs内的10个氨基酸的插入鸟分枝杆菌和胞内分枝杆菌可以是这两个物种间到Q203的自然性的合理的解释。