Chlamydia trachomatis is a strict intracellular bacterium that causes sexually transmitted infections and eye infections that can lead to lifelong sequelae. Treatment options are limited to broad-spectrum antibiotics that disturb the commensal flora and contribute to selection of antibiotic-resistant bacteria. Hence, development of novel drugs that specifically target C. trachomatis would be beneficial. 2-Pyridone amides are potent and specific inhibitors of Chlamydia infectivity. The first-generation compound KSK120 inhibits the developmental cycle of Chlamydia, resulting in reduced infectivity of progeny bacteria. Here, we show that the improved, highly potent second-generation 2-pyridone amide KSK213 allowed normal growth and development of C. trachomatis, and the effect was only observable upon reinfection of new cells. Progeny elementary bodies (EBs) produced in the presence of KSK213 were unable to activate transcription of essential genes in early development and did not differentiate into the replicative form, the reticulate body (RB). The effect was specific to C. trachomatis since KSK213 was inactive in the closely related animal pathogen Chlamydia muridarum and in Chlamydia caviae. The molecular target of KSK213 may thus be different in C. trachomatis or nonessential in C. muridarum and C. caviae. Resistance to KSK213 was mediated by a combination of amino acid substitutions in both DEAD/DEAH RNA helicase and RNase III, which may indicate inhibition of the transcriptional machinery as the mode of action. 2-Pyridone amides provide a novel antibacterial strategy and starting points for development of highly specific drugs for C. trachomatis infections.

中文翻译：

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沙眼衣原体转录活性的 2-吡啶酮酰胺抑制剂

沙眼衣原体是一种严格的细胞内细菌，会导致性传播感染和眼部感染，从而导致终生后遗症。治疗选择仅限于广谱抗生素，这些抗生素会扰乱共生菌群并有助于选择抗生素耐药细菌。因此，开发专门针对沙眼衣原体的新型药物将是有益的。2-吡啶酮酰胺是衣原体感染性的有效和特异性抑制剂。第一代化合物 KSK120 抑制衣原体的发育周期，导致后代细菌的感染力降低。在这里，我们证明改进的、高效的第二代 2-吡啶酮酰胺 KSK213 允许正常生长和发育C. trachomatis，并且只有在重新感染新细胞时才能观察到效果。在 KSK213 存在的情况下产生的后代基本体 (EB) 无法在早期发育中激活必需基因的转录，并且不会分化为复制形式，即网状体 (RB)。由于 KSK213 在密切相关的动物病原体Chlamydia muridarum和Chlamydia caviae中没有活性，因此该作用对沙眼衣原体具有特异性。因此，KSK213 的分子靶标在沙眼衣原体中可能不同，或者在鼠尾隐球菌和豚鼠衣原体中不是必需的. 对 KSK213 的抗性是由 DEAD/DEAH RNA 解旋酶和 RNase III 中的氨基酸替换组合介导的，这可能表明转录机制的抑制是作用方式。2-吡啶酮酰胺提供了一种新的抗菌策略，并为开发针对沙眼衣原体感染的高度特异性药物提供了起点。