Grim Kyle P, Radin Jana N, Solórzano Paola K Párraga, Morey Jacqueline R, Frye Katie A, Ganio Katherine, Neville Stephanie L, McDevitt Christopher A, Kehl-Fie Thomas E
Department of Microbiology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA.
Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA.
J Bacteriol. 2020 Apr 9;202(9). doi: 10.1128/JB.00014-20.
The host restricts the availability of zinc to prevent infection. To overcome this defense, and rely on zincophore-dependent zinc importers. Synthesis of the zincophore staphylopine by and its import are both necessary for the bacterium to cause infection. In this study, we sought to elucidate how loss of zincophore efflux impacts bacterial resistance to host-imposed zinc starvation. In culture and during infection, mutants lacking CntE, the staphylopine efflux pump, were more sensitive to zinc starvation imposed by the metal-binding immune effector calprotectin than those lacking the ability to import staphylopine. However, disruption of staphylopine synthesis reversed the enhanced sensitivity phenotype of the Δ mutant to calprotectin, indicating that intracellular toxicity of staphylopine is more detrimental than the impaired ability to acquire zinc. Unexpectedly, intracellular accumulation of staphylopine does not increase the expression of metal importers or alter cellular metal concentrations, suggesting that, contrary to prevailing models, the toxicity associated with staphylopine is not strictly due to intracellular chelation of metals. As and other pathogens produce zincophores with similar chemistry, our observations on the crucial importance of zincophore efflux are likely to be broadly relevant. and many other bacterial pathogens rely on metal-binding small molecules to obtain the essential metal zinc during infection. In this study, we reveal that export of these small molecules is critical for overcoming host-imposed metal starvation during infection and prevents toxicity due to accumulation of the metal-binding molecule within the cell. Surprisingly, we found that intracellular toxicity of the molecule is not due to chelation of cellular metals.
宿主限制锌的可用性以防止感染。为了克服这种防御机制，（细菌）依赖锌载体依赖性锌转运体。由（细菌）合成锌载体葡萄球菌碱及其导入对于细菌引起感染都是必要的。在本研究中，我们试图阐明锌载体外排的丧失如何影响细菌对宿主施加的锌饥饿的抗性。在培养和感染过程中，缺乏葡萄球菌碱外排泵CntE的突变体比缺乏导入葡萄球菌碱能力的突变体对金属结合免疫效应分子钙卫蛋白施加的锌饥饿更敏感。然而，葡萄球菌碱合成的破坏逆转了Δ突变体对钙卫蛋白的增强敏感性表型，表明葡萄球菌碱的细胞内毒性比获取锌能力受损更具危害性。出乎意料的是，葡萄球菌碱的细胞内积累不会增加金属转运体的表达或改变细胞金属浓度，这表明与普遍模型相反，与葡萄球菌碱相关的毒性并不严格归因于细胞内金属螯合。由于（该细菌）和其他病原体产生具有相似化学性质的锌载体，我们关于锌载体外排至关重要性的观察结果可能具有广泛的相关性。（该细菌）和许多其他细菌病原体在感染期间依赖金属结合小分子来获取必需金属锌。在本研究中，我们揭示这些小分子的输出对于在感染期间克服宿主施加的金属饥饿至关重要，并防止由于金属结合分子在细胞内积累而产生的毒性。令人惊讶的是，我们发现该分子的细胞内毒性不是由于细胞金属螯合。
