Each year in the United States, infections by methicillin-resistant Staphylococcus aureus (MRSA) are responsible for ∼19,000 deaths and result in $3-$4 billion of health care costs. Because skin colonization is a major risk factor for S. aureus infection, identifying novel small molecules produced by S. aureus can lead to new molecular insights into its ability to colonize and infect the host and new targets for antibacterial intervention. Here, we report that a nonribosomal peptide synthetase conserved across S. aureus and other skin-associated staphylococci encodes a family of three pyrazinone natural products. These molecules likely result from the synthesis and release of a dipeptide aldehyde, its spontaneous cyclization to a dihydropyrazinone, and subsequent oxidation to a pyrazinone. As an unexpected family of small molecule natural products from the pathogen S. aureus, the pyrazinones may open a new window into the interspecies interactions that underlie the poorly understood process of skin colonization.
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