The production of most Staphylococcus aureus virulence factors and other exoproteins is controlled by a complex polycistronic regulatory locus known as agr. The agr system is unique among global regulons in that its regulatory effector is an RNA molecule. In preliminary studies, we have cloned and sequenced the agr locus and determined its basic functional organization. The locus consists of two divergent operons transcribed from promoters P2 & P3. The 3 kb P2 operon contains 4 open reading frames of which two resemble the two components of the bacterial sensory transduction systems. The 0.5 kb transcript of the P3 operon is the regulatory RNAIII, which incidentally contains the coding sequence for one of the agrregulated exoproteins, delta-hemolysin. The agr-determined sensory transduction pathway, activated during mid-exponential phase by an unknown metabolic signal, functions solely to activate transcription from P2 and P3, setting up an internal auto-catalytic regulatory circuit Translation and secretion of the regulated products occur post-exponentially, some 2h after the initiation of transcription. A comprehensive analysis of the agr system is proposed, focusing on the structure and functions of RNAIII. The mechanism of transcriptional activation by the P2 operon products will also be investigated and an attempt will be made to identify the determinants of the apparently biphasic temporal response. This program has implications for the understanding of bacterial pathogenicity and it constitutes an entry into the broader area of temporal regulation of genetic function.
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