Mycobacterium tuberculosis (Mtb) is the aetiological agent of tuberculosis, the leading cause of death worldwide from a single infectious agent. Mtb is a highly adaptable human pathogen that might enter a dormant non-replicating (NR), drug-tolerant stage. Reactivation of dormant Mtb can lead to active disease. Antibiotic treatments of active and latent tuberculosis are long, complex and may fail to fully eradicate the infection. Therefore, it is imperative to identify novel compounds with new mechanisms of action active against NR bacilli. Dormant Mtb habitat is mostly thought to be the pH-neutral and hypoxic caseous granuloma. We have used the Wayne culture model to reproduce this environment and tested the activities of two DNA-targeted agents, C8-linked-pyrrolobenzodiazepine(PBD)-polyamide conjugates 1 and 2, against Mtb grown in aerobic and hypoxic conditions in both acidic and pH-neutral media. PBD 2 showed growth inhibitory activity at 5.1 µg/ml against 19-day-old hypoxic NR Mtb cultures with 1.8 log₁₀ CFU reduction on day 21 at pH 7.3. PBD 2 was particularly effective against 5-day-old aerobic cells at pH 7.3, with CFU reduction (>6.8 log₁₀) on day 21 at 5.1 µg/ml being identical to that of rifampin at 8 µg/ml. PBD 2 qualifies as a promising lead against aerobic and NR Mtb.

中文翻译：

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在酸性和中性条件下，靶向DNA的C8连接的吡咯并苯并二氮杂杂环杂环共轭物对需氧和缺氧生长的结核分枝杆菌的活性。

结核分枝杆菌（Mtb）是结核病的病原体，是全球一种传染病致死的主要原因。Mtb是一种高度适应性的人类病原体，可能会进入休眠的非复制（NR），药物耐受期。休眠Mtb的重新激活可能导致活动性疾病。活动性和潜伏性结核的抗生素治疗时间长，复杂，可能无法完全根除感染。因此，必须确定具有新的作用于NR细菌的新作用机制的化合物。人们通常认为休眠Mtb栖息地是pH中性和缺氧的干酪性肉芽肿。我们已经使用Wayne培养模型重现了这种环境，并测试了两种以DNA为目标的药物C8连接的吡咯并苯并二氮杂（PBD）-聚酰胺共轭物1和2的活性。在有氧和低氧条件下在酸性和pH中性培养基中生长的抗Mtb。PBD 2对19天龄低氧NR Mtb培养物（对数为1.8 log）的生长抑制活性为5.1 µg / ml在pH 7.3下在第21天降低₁₀ CFU。PBD 2对pH值为7.3的5天龄需氧细胞特别有效，第21天CFU降低（> 6.8 log ₁₀）的浓度为5.1 µg / ml，与利福平的浓度相同，为8 µg / ml。PBD 2有资格成为有氧和NR Mtb的有前途的领先者。