An unprecedented small RNA-riboswitch interaction controls the expression of a bifunctional pump essential for Staphylococcus aureus infection

Maintaining manganese and iron homeostasis is critical for the human pathogen Staphylococcus aureus. To counteract metal-based host defense strategies, S. aureus uses a combination of metal-sensing transcription factors and regulatory RNAs to maintain metal homeostasis. Here, we uncovered an unprecedented interaction between a cis- and a trans-acting regulatory RNAs controlling a conditionally essential gene, mntY, encoding a Mn efflux pump. This conserved RNA-RNA interaction between a Fe-responsive sRNA and a Mn-sensing riboswitch allows the integration of Fe- and Mn-related stresses to fine-tune mntY expression. We demonstrated a dual role for MntY in metalation of Mn-dependent exoenzymes and Mn detoxification, which is critical for S. aureus adaptation to both low and high Mn environments. Deletion of the mntY gene is strongly pleomorphic, causing growth defects, altering virulence factor expression, immune evasion, and survival during infection. These findings point to MntY as a promising new therapeutic target to combat multidrug-resistant staphylococcal infections.