A Zur-dependent regulatory RNA involved in maintaining zinc homeostasis in Staphylococcus aureus

Small regulatory RNAs (sRNAs) are key drivers of bacterial adaptation to environmental fluctuations, including iron and manganese restriction imposed by the host. This study explored the repertoire of sRNAs produced by the human pathogen Staphylococcus aureus in response to metal limitation. Two sRNAs were identified, S1077 and ZinS, that were regulated by zinc (Zn) availability. Further investigations revealed that, similar to the cnt operon from which it derives, S1077 synthesis is controlled by the transcription factors Zur and Fur. In contrast, zinS transcription is solely repressed by Zur. RNA affinity purification identified several ZinS-associated mRNAs encoding Zn-dependent enzymes, including the alcohol dehydrogenase Adh, whose synthesis is negatively regulated by ZinS. Loss of ZinS does not alter staphylococcal metal accumulation, suggesting a role in a Zn-sparing response. Remarkably, zinS also encodes a small peptide, ZinP. Genomic analysis shows that the regulatory portion of zinS emerged from the 3' untranslated region of zinP and is conserved in S. aureus and closely related species, whereas zinP is also found in phylogenetically distant organisms. Our findings demonstrate that sRNAs facilitate bacterial adaptation to Zn limitation, and that genetic exchange and subsequent neofunctionalization have enabled S. aureus to adapt to metal-restricted environments.