Bacterial type II topoisomerases, DNA gyrase and topoisomerase IV, are targets of many antibiotics, including fluoroquinolones (FQs). Unfortunately, a number of bacterial species easily acquire resistance to FQs by mutations in either DNA gyrase or topoisomerase IV genes. The emergence of resistant pathogenic strains is a global problem in health care; therefore, identifying alternative pathways to thwart their persistence is the current frontier in drug discovery. Nybomycins are an attractive class of compounds, reported to be “reverse antibiotics” that selectively inhibit growth of some Gram-positive FQ-resistant bacteria by targeting the mutant form of DNA gyrase while being inactive against wild-type strains with FQ-sensitive gyrases. The strong “reverse” effect was demonstrated only for a few Gram-positive organisms resistant to FQs due to the S83L/I mutation in the GyrA subunit of DNA gyrase. However, the activity of nybomycins has not been extensively explored among Gram-negative species. Here, we observed that in a ΔtolC strain of the Gram-negative Escherichia coli with enhanced permeability, wild-type gyrase and a GyrA S83L mutant, resistant to fluoroquinolones, are similarly sensitive to nybomycin.

中文翻译：

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Nybomycin 抑制对氟喹诺酮敏感和对氟喹诺酮耐药的大肠杆菌 DNA 促旋酶

细菌 II 型拓扑异构酶、DNA 促旋酶和拓扑异构酶 IV 是许多抗生素的靶标，包括氟喹诺酮类 (FQ)。不幸的是，许多细菌物种很容易通过 DNA 促旋酶或拓扑异构酶 IV 基因的突变获得对 FQ 的抗性。耐药致病菌株的出现是医疗保健领域的一个全球性问题；因此，确定阻止其持久存在的替代途径是药物发现的当前前沿。Nybomycins 是一类有吸引力的化合物，据报道是“反向抗生素”，它通过靶向 DNA 促旋酶的突变形式选择性地抑制一些革兰氏阳性 FQ 抗性细菌的生长，同时对具有 FQ 敏感促旋酶的野生型菌株无活性。由于 DNA 促旋酶的 GyrA 亚基中的 S83L/I 突变，仅对少数对 FQ 具有抗性的革兰氏阳性生物体证明了强烈的“反向”作用。然而，尚未在革兰氏阴性菌种中广泛探索尼波霉素的活性。在这里，我们观察到在 Δ革兰氏阴性大肠杆菌的tolC菌株具有增强的通透性、野生型促旋酶和 GyrA S83L 突变体，对氟喹诺酮类药物具有抗性，对尼波霉素同样敏感。