Nishino Kunihiko, Hsu Fong-Fu, Turk John, Cromie Michael J, Wösten Marc M S M, Groisman Eduardo A
Department of Molecular Microbiology, Howard Hughes Medical Institute, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Mol Microbiol. 2006 Aug;61(3):645-54. doi: 10.1111/j.1365-2958.2006.05273.x. Epub 2006 Jun 27.
Iron is an essential metal but can be toxic in excess. While several homeostatic mechanisms prevent oxygen-dependent killing promoted by Fe(II), little is known about how cells cope with Fe(III), which kills by oxygen-independent means. Several Gram-negative bacterial species harbour a regulatory system - termed PmrA/PmrB - that is activated by and required for resistance to Fe(III). We now report the identification of the PmrA-regulated determinants mediating resistance to Fe(III) and Al(III) in Salmonella enterica serovar Typhimurium. We establish that these determinants remodel two regions of the lipopolysaccharide, decreasing the negative charge of this major constituent of the outer membrane. Remodelling entails the covalent modification of the two phosphates in the lipid A region with phosphoethanolamine and 4-aminoarabinose, which has been previously implicated in resistance to polymyxin B, as well as dephosphorylation of the Hep(II) phosphate in the core region by the PmrG protein. A mutant lacking the PmrA-regulated Fe(III) resistance genes bound more Fe(III) than the wild-type strain and was defective for survival in soil, suggesting that these PmrA-regulated lipopolysaccharide modifications aid Salmonella's survival and spread in non-host environments.
铁是一种必需金属，但过量时可能具有毒性。虽然有几种稳态机制可防止由Fe(II)促进的氧依赖性杀伤，但对于细胞如何应对通过非氧依赖性方式杀伤的Fe(III)却知之甚少。几种革兰氏阴性细菌物种拥有一种称为PmrA/PmrB的调节系统，该系统被对Fe(III)的抗性激活且是其必需的。我们现在报告在鼠伤寒沙门氏菌中鉴定出介导对Fe(III)和Al(III)抗性的PmrA调节决定因素。我们确定这些决定因素重塑脂多糖的两个区域，降低外膜这一主要成分的负电荷。重塑需要用磷酸乙醇胺和4-氨基阿拉伯糖对脂质A区域中的两个磷酸盐进行共价修饰，这两种物质先前已被证明与对多粘菌素B的抗性有关，以及通过PmrG蛋白使核心区域中的Hep(II)磷酸盐去磷酸化。一个缺乏PmrA调节的Fe(III)抗性基因的突变体比野生型菌株结合更多的Fe(III)，并且在土壤中生存存在缺陷，这表明这些PmrA调节的脂多糖修饰有助于沙门氏菌在非宿主环境中的生存和传播。
