A small protein that mediates the activation of a two-component system by another two-component system

The PmrA–PmrB two‐component system of Salmonella enterica controls resistance to the peptide antibiotic polymyxin B and to several antimicrobial proteins from human neutrophils. Transcription of PmrA‐activated genes is induced by high iron, but can also be promoted by growth in low magnesium in a process that requires another two‐component system, PhoP–PhoQ. Here, we define the genetic basis for the interaction between the PhoP–PhoQ and PmrA–PmrB systems. We have identified pmrD as a PhoP‐activated gene that mediates the transcriptional activation of PmrA‐regulated genes during growth in low magnesium. When transcription of pmrD is driven from a heterologous promoter, expression of PmrA‐activated genes occurs even at repressing magnesium concentrations and becomes independent of the phoP and phoQ genes. The PmrD effect is specific for PmrA‐regulated genes and requires functional PmrA and PmrB proteins. A pmrD mutant is sensitive to polymyxin if grown in low magnesium, but resistant if grown in high iron. The PmrD protein controls the activity of the PmrA–PmrB system at a post‐transcriptional level.