Metal homeostasis and resistance in bacteria

Key Points Specific protein-based and riboswitch-based metal sensors monitor the intracellular levels of metal ions and regulate the expression of pathways for uptake, storage and efflux, as well as alternative enzymes that use a different metal or non-metal cofactor. Transcription factors often mediate graded responses in which different genes are regulated at different levels of signal. Metal ions are required for growth, with cellular concentrations of Zn( II ), Mn( II ) and Fe between 0.4–1 mM under sufficient conditions. Metals are present in metalloenzymes, which are stored in membrane or protein compartments, and are present in a low-molecular-weight labile pool. Inhibition of bacterial growth due to metal limitation often occurs as a result of the failure of metal-dependent enzymes. Inhibition of bacterial growth due to metal intoxication can involve the production of harmful reactive oxygen species and/or the incorrect metallation of enzymes that are involved in key metabolic pathways. The host immune system has evolved to take advantage of both metal limitation ('nutritional immunity') and metal intoxication as methods of responding to infection. Metal limitation and intoxication are evolutionarily conserved mechanisms that are used by protozoa and higher eukaryotes to kill bacteria. In this Review, Chandrangsu et al . discuss recent insights into metalloregulatory systems that are used by bacteria and how they respond to metal limitation and intoxication, as well as how these systems influence host–pathogen interactions. Metal ions are essential for many reactions, but excess metals can be toxic. In bacteria, metal limitation activates pathways that are involved in the import and mobilization of metals, whereas excess metals induce efflux and storage. In this Review, we highlight recent insights into metal homeostasis, including protein-based and RNA-based sensors that interact directly with metals or metal-containing cofactors. The resulting transcriptional response to metal stress takes place in a stepwise manner and is reinforced by post-transcriptional regulatory systems. Metal limitation and intoxication by the host are evolutionarily ancient strategies for limiting bacterial growth. The details of the resulting growth restriction are beginning to be understood and seem to be organism-specific.