Department of Biology, Tor Vergata University of Rome, Rome, Italy.
Department of Chemistry, Sapienza University of Rome, Rome, Italy.
mBio. 2024 Oct 16;15(10):e0239524. doi: 10.1128/mbio.02395-24. Epub 2024 Sep 24.
Limiting the availability of transition metals at infection sites serves as a critical defense mechanism employed by the innate immune system to combat microbial infections. exhibits a remarkable ability to thrive in zinc-deficient environments, facilitated by intricate cellular responses governed by numerous genes regulated by the zinc-responsive transcription factor Zur. Many of these genes have unknown functions, including those within the predicted and operons. A structural bioinformatics investigation revealed that comprises a TonB-dependent outer membrane receptor and inner membrane ABC-permeases responsible for importing metal-chelating molecules, whereas contains genes encoding a MacB transporter, likely involved in the export of large molecules. Molecular genetics and biochemical experiments, feeding assays, and intracellular metal content measurements support the hypothesis that and are engaged in the import and export of the pyochelin-cobalt complex, respectively. Notably, cobalt can reduce zinc demand and promote the growth of strains unable to import zinc, highlighting pyochelin-mediated cobalt import as a novel bacterial strategy to counteract zinc deficiency. These results unveil an unexpected role for pyochelin in zinc homeostasis and challenge the traditional view of this metallophore exclusively as an iron transporter.
The mechanisms underlying the remarkable ability of to resist the zinc sequestration mechanisms implemented by the vertebrate innate immune system to control bacterial infections are still far from being fully understood. This study reveals that the Zur-regulated gene clusters and encode systems for the import and export of cobalt-bound pyochelin, respectively. This proves to be a useful strategy to counteract conditions of severe zinc deficiency since cobalt can replace zinc in many proteins. The discovery that pyochelin may contribute to cellular responses to zinc deficiency leads to a reevaluation of the paradigm that pyochelin is a siderophore involved exclusively in iron acquisition and suggests that this molecule has a broader role in modulating the homeostasis of multiple metals.
限制感染部位过渡金属的可用性是先天免疫系统用来对抗微生物感染的关键防御机制。 表现出在缺锌环境中茁壮成长的非凡能力，这得益于受锌反应转录因子 Zur 调节的众多基因控制的复杂细胞反应。这些基因中的许多具有未知的功能，包括预测的 和 操纵子中的基因。结构生物信息学研究表明， 由 TonB 依赖性外膜受体和内膜 ABC 转运蛋白组成，负责导入金属螯合分子，而 包含编码 MacB 转运蛋白的基因，可能参与大分子的输出。分子遗传学和生化实验、喂养实验和细胞内金属含量测量支持这样的假设，即 和 分别参与了焦脱酚-钴复合物的导入和导出。值得注意的是，钴可以降低锌的需求并促进不能导入锌的 菌株的生长，这突出了焦脱酚介导的钴导入作为细菌对抗缺锌的一种新策略。这些结果揭示了焦脱酚在锌动态平衡中的意外作用，并挑战了这种金属载体仅作为铁转运蛋白的传统观点。
仍然远未完全理解 抵抗脊椎动物先天免疫系统实施的锌螯合机制的非凡能力的机制。本研究表明，Zur 调节的基因簇 和 分别编码钴结合焦脱酚的导入和导出系统。这被证明是一种对抗严重缺锌的有用策略，因为钴可以替代许多蛋白质中的锌。发现焦脱酚可能有助于细胞对锌缺乏的反应，导致重新评估焦脱酚是一种仅参与铁获取的铁载体的范式，并表明该分子在调节多种金属的动态平衡方面具有更广泛的作用。
