One of the most commonly prescribed antibiotics against Burkholderia infections is co‐trimoxazole, a cocktail of trimethoprim and sulfamethoxazole. Trimethoprim elicits an upregulation of the mal gene cluster, which encodes proteins involved in synthesis of the cytotoxic polyketide malleilactone; trimethoprim does so by increasing expression of the malR gene, which encodes the activator MalR. We report that B. thailandensis grown on trimethoprim exhibited increased virulence against Caenorhabditis elegans. This enhanced virulence correlated with an increase in expression of the mal gene cluster. Notably, inhibition of xanthine dehydrogenase by addition of allopurinol led to similar upregulation of malA and malR, with addition of trimethoprim or allopurinol also resulting in an equivalent intracellular accumulation of xanthine. Xanthine is a ligand for the transcription factor MftR that leads to attenuated DNA binding, and we show using chromatin immunoprecipitation that MftR binds directly to malR. Our gene expression data suggest that malR expression is repressed by both MftR and by a separate transcription factor, which also responds to a metabolite that accumulates on exposure to trimethoprim. Since allopurinol elicits a similar increase in malR/malA expression as trimethoprim, we suggest that impaired purine homeostasis plays a primary role in trimethoprim‐mediated induction of malR and in turn malA.

中文翻译：

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受损的嘌呤稳态在甲氧苄啶介导的泰国伯克霍尔德菌毒力基因诱导中起主要作用

抗伯克霍尔德菌感染最常用的抗生素之一是复方新诺明，一种甲氧苄氨嘧啶和磺胺甲恶唑的混合物。甲氧苄氨嘧啶引起mal基因簇的上调，该簇编码参与细胞毒性聚酮内酯合成的蛋白质；甲氧苄氨嘧啶是通过增加编码激活剂 MalR的malR基因的表达来实现的。我们报告说，在甲氧苄啶上生长的B. thailandensis表现出对秀丽隐杆线虫的毒力增加。这种增强的毒力与mal表达的增加相关基因簇。值得注意的是，通过添加别嘌呤醇抑制黄嘌呤脱氢酶导致了类似的malA和malR上调，添加甲氧苄氨嘧啶或别嘌呤醇也导致等效的细胞内黄嘌呤积累。黄嘌呤是转录因子 MftR 的配体，可导致 DNA 结合减弱，我们使用染色质免疫沉淀表明 MftR 直接与malR结合。我们的基因表达数据表明，malR表达被 MftR 和单独的转录因子抑制，后者也对暴露于甲氧苄啶时积累的代谢物有反应。由于别嘌呤醇引起malR/malA的类似增加表达为甲氧苄氨嘧啶，我们认为受损的嘌呤稳态在甲氧苄啶介导的malR和malA的诱导中起主要作用。