In this work, we present the first inhibitor of GlnA2Sc, a gamma-glutamylpolyamine synthetase, which allows S. coelicolor to detoxify high concentrations of polyamines and to utilize them as a carbon or nitrogen source. GlnA2 belongs to the class of glutamine-synthetase-like (GS-like) enzymes that catalyze the glutamylation of different nitrogen-containing compounds. Whereas a number of inhibitors for glutamine synthetases are known, none of them are known to inhibit GlnA2. In this work, PPU 268 an inhibitor for GlnA2 is presented that is structurally derived from the prototypic GS inhibitor—methionine sulfoximine (MSO). It combines two features: the binding mechanism of MSO and the amine substrate specificity of GlnA2Sc. This inhibitor is a novel compound to block the polyamine utilization in bacteria resulting in the inability to detoxify polyamines. This may offer a possibility to develop novel therapeutic strategies to combat actinobacterial human pathogens that encounter polyamines in the course of the infection processes.

中文翻译：

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天蓝色链球菌多胺利用的新型合成抑制剂

在这项工作中，我们提出了 GlnA2Sc（一种 γ-谷氨酰多胺合成酶）的第一种抑制剂，它允许天蓝色链球菌解毒高浓度的多胺并将其用作碳源或氮源。GlnA2 属于谷氨酰胺合成酶样（GS 样）酶，可催化不同含氮化合物的谷氨酰化。尽管已知有多种谷氨酰胺合成酶抑制剂，但没有一种已知可以抑制 GlnA2。在这项工作中，PPU 268 是一种 GlnA2 抑制剂，其结构源自原型 GS 抑制剂——甲硫氨酸亚砜亚胺 (MSO)。它结合了两个特点：MSO 的结合机制和 GlnA2Sc 的胺底物特异性。这种抑制剂是一种新型化合物，可阻止细菌利用多胺，导致细菌无法解毒多胺。这可能为开发新的治疗策略来对抗在感染过程中遇到多胺的放线菌人类病原体提供了可能性。