School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Australia.
Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.
mSphere. 2021 May 19;6(3):e00105-21. doi: 10.1128/mSphere.00105-21.
Zinc is an essential trace element for normal bacterial physiology but, divergently, can intoxicate bacteria at high concentrations. Here, we define the molecular systems for Zn detoxification in , also known as group B streptococcus, and examine the effects of resistance to Zn stress on virulence. We compared the growth of wild-type bacteria and mutants deleted for the Zn exporter, , and the response regulator, , using Zn-stress conditions Macrophage antibiotic protection assays and a mouse model of disseminated infection were used to assess virulence. Global bacterial transcriptional responses to Zn stress were defined by RNA sequencing and quantitative reverse transcription-PCR. and enabled to survive Zn stress, with the putative CzcD efflux system activated by SczA. Additional genes activated in response to Zn stress encompassed divalent cation transporters that contribute to regulation of Mn and Fe homeostasis. , the - Zn management axis supported virulence in the blood, heart, liver, and bladder. Additionally, several genes not previously linked to Zn stress in any bacterium, including, most notably, for arginine deamination, also mediated resistance to Zn stress, representing a novel molecular mechanism of bacterial resistance to metal intoxication. Taken together, these findings show that responds to Zn stress by regulation of , with additional novel mechanisms of resistance supported by , encoding arginine deaminase. Cellular management of Zn stress in supports virulence by facilitating bacterial survival in the host during systemic infection., also known as group B streptococcus, is an opportunistic pathogen that causes various diseases in humans and animals. This bacterium has genetic systems that enable zinc detoxification in environments of metal stress, but these systems remain largely undefined. Using a combination of genomic, genetic, and cellular assays, we show that this pathogen controls Zn export through CzcD to manage Zn stress and utilizes a system of arginine deamination never previously linked to metal stress responses in bacteria to survive metal intoxication. We show that these systems are crucial for survival of during Zn stress and also enhance virulence during systemic infection in mice. These discoveries establish new molecular mechanisms of resistance to metal intoxication in bacteria; we suggest these mechanisms operate in other bacteria as a way to sustain microbial survival under conditions of metal stress, including in host environments.
锌是正常细菌生理所必需的微量元素，但在高浓度下，锌会使细菌中毒。在这里，我们定义了 ，也称为 B 群链球菌，中的锌解毒分子系统，并研究了对锌胁迫的抗性对毒力的影响。我们比较了野生型细菌和缺失锌外排体 和应答调节剂 的突变体的生长情况，使用锌胁迫条件下 进行了巨噬细胞抗生素保护测定和小鼠弥散性感染模型来评估毒力。通过 RNA 测序和定量逆转录-PCR 定义了细菌对锌胁迫的全基因组转录反应。 和 使 能够耐受锌胁迫，推测由 SczA 激活 CzcD 外排系统。对锌胁迫反应激活的其他基因包括二价阳离子转运体，有助于调节锰和铁的稳态。 - Zn 管理轴在血液、心脏、肝脏和膀胱中支持毒力。此外，一些以前与任何细菌的锌胁迫都没有联系的基因，包括 ，特别是用于精氨酸脱氨酶的 ，也介导了对锌胁迫的抗性，这代表了细菌对金属中毒的一种新的分子机制。总之，这些发现表明， 通过 调节对锌胁迫作出反应， 通过编码精氨酸脱氨酶的 提供了额外的抗性新机制。 在宿主中系统感染期间，锌应激的细胞管理通过促进细菌存活来支持毒力。 ，也称为 B 群链球菌，是一种机会性病原体，可引起人和动物的各种疾病。这种细菌具有使锌在金属应激环境中解毒的遗传系统，但这些系统在很大程度上尚未确定。我们使用基因组、遗传和细胞测定的组合表明，这种病原体通过 CzcD 控制锌外排以应对 Zn 应激，并利用一种以前从未与细菌的金属应激反应联系起来的精氨酸脱氨酶系统来在金属中毒中存活。我们表明，这些系统对 在 Zn 应激下的存活至关重要，并且在小鼠系统性感染期间也增强了毒力。这些发现为细菌金属中毒抗性建立了新的分子机制；我们建议这些机制在其他细菌中起作用，以在金属应激条件下维持微生物的存活，包括在宿主环境中。
