Mycobacterium tuberculosis (Mtb) is a pathogenic bacterium that caused 1.5 million fatalities globally in 2018. New strains of Mtb resistant to all known classes of antibiotics pose a global healthcare problem. In this work, we have conjugated novel indole-3-acetic acid-based DNA primase/gyrase inhibitor with cell-penetrating peptide via cleavable and non-cleavable bonds. For non-cleavable linkage, inhibitor was conjugated with peptide via an amide bond to the N-terminus, whereas a cleavable linkage was obtained by conjugating the inhibitor through a disulfide bond. We performed the conjugation of the inhibitor either directly on a solid surface or by using solution-phase chemistry. M. smegmatis (non-pathogenic model of Mtb) was used to determine the minimal inhibitory concentration (MIC) of the synthetic conjugates. Conjugates were found more active as compared to free inhibitor molecules. Strikingly, the conjugate also impairs the development of biofilm, showing a therapeutic potential against infections caused by both planktonic and sessile forms of mycobacterium species.

中文翻译：

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基于吲哚-3-乙酸的 DNA 引物酶/旋转酶抑制剂的细胞穿透肽偶联物作为有效的抗结核剂对耻垢分枝杆菌浮游和生物膜培养物

结核分枝杆菌( Mtb ) 是一种致病细菌，2018 年在全球造成 150 万人死亡。对所有已知类别的抗生素耐药的新Mtb菌株构成了全球医疗保健问题。在这项工作中，我们通过可切割和不可切割的键将新型基于吲哚-3-乙酸的 DNA 引物/促旋酶抑制剂与细胞穿透肽结合。对于不可切割的连接，抑制剂通过酰胺键与肽结合到 N 末端，而可切割的连接是通过将抑制剂通过二硫键结合来获得的。我们直接在固体表面上或通过使用溶液相化学进行抑制剂的缀合。耻垢分枝杆菌（ Mtb的非致病性模型) 用于确定合成缀合物的最小抑制浓度 (MIC)。发现缀合物与游离抑制剂分子相比更具活性。引人注目的是，该缀合物还损害生物膜的发育，显示出对由浮游和固着形式的分枝杆菌引起的感染的治疗潜力。