The molecular evolution of the adaptive response at the host–pathogen interface has been frequently referred to as an 'arms race' between the host and bacterial pathogens. The innate immune system employs multiple strategies to starve microbes of metals. Pathogens, in turn, develop successful strategies to maintain access to bioavailable metal ions under conditions of extreme restriction of transition metals, or nutritional immunity. However, the processes by which evolution repurposes or re-engineers host and pathogen proteins to perform or refine new functions have been explored only recently. Here we review the molecular evolution of several human metalloproteins charged with restricting bacterial access to transition metals. These include the transition metal-chelating S100 proteins, natural resistance-associated macrophage protein-1 (NRAMP-1), transferrin, lactoferrin, and heme-binding proteins. We examine their coevolution with bacterial transition metal acquisition systems, involving siderophores and membrane-spanning metal importers, and the biological specificity of allosteric transcriptional regulatory proteins tasked with maintaining bacterial metallostasis. We also discuss the evolution of metallo-β-lactamases; this illustrates how rapid antibiotic-mediated evolution of a zinc metalloenzyme obligatorily occurs in the context of host-imposed nutritional immunity.

宿主-病原体界面适应性反应的分子进化经常被称为宿主和细菌病原体之间的“军备竞赛”。先天免疫系统采用多种策略来使微生物缺乏金属。反过来，病原体在过度限制过渡金属或营养免疫的条件下，制定了成功的策略来维持对生物可利用的金属离子的获取。然而，进化重新利用或重新设计宿主和病原体蛋白质以执行或完善新功能的过程直到最近才被探索。在这里，我们回顾了几种负责限制细菌接触过渡金属的人类金属蛋白的分子进化。其中包括过渡金属螯合 S100 蛋白、天然抗性相关巨噬细胞蛋白 1 (NRAMP-1)、转铁蛋白、乳铁蛋白和血红素结合蛋白。我们研究了它们与细菌过渡金属获取系统的共同进化，包括铁载体和跨膜金属输入器，以及负责维持细菌金属稳态的变构转录调节蛋白的生物特异性。我们还讨论了金属-β-内酰胺酶的进化；这说明了在宿主施加的营养免疫的背景下，抗生素介导的锌金属酶的快速进化是如何必然发生的。