Characterization of the Staphylococcus aureus CidR regulon:: elucidation of a novel role for acetoin metabolism in cell death and lysis

The Staphylococcus aureus cid and lrg operons encode a novel regulatory system that affects murein hydrolase activity, stationary-phase survival and antibiotic tolerance. Expression of the lrgAB operon is positively regulated by a two-component regulatory system encoded by the lytSR operon located immediately upstream to lrgAB. By comparison, the cidABC operon lies downstream from the cidR gene, encoding a protein homologous to the LysR-type family of transcriptional regulators. Transcription analysis of a cidR mutant revealed that CidR enhances cidABC expression in the presence of acetic acid generated by the metabolism of excess glucose. Microarray studies identified additional CidR-regulated operons including the IrgAB and alsSD encoding proteins involved in acetoin production. Surprisingly, Northern blot analyses revealed that cidABC and lrgAB transcription was uninducible in an alsSD mutant grown in the presence of excess glucose, suggesting that the CidR-mediated upregulation of cidABC and lrgAB transcription is dependent on the presence of intact alsSD genes. Zymographic and quantitative analyses of murein hydrolase activity also revealed that disruption of the alsSD genes results in significantly decreased extracellular murein hydrolase activity compared with that of the parental strain, UAMS-1. Furthermore, the alsSD mutant displayed decreased stationary-phase survival relative to UAMS-1, both in the presence and absence of glucose. The results of this study define the CidR regulon and demonstrate that the generation of acetoin is linked to the control of cell death and lysis in S. aureus.