Staphylococcus aureus accessory gene regulator–phenol-soluble modulin alpha virulence pathway (agr–psmα pathway)

The Staphylococcus aureus accessory gene regulator (agr)–phenol-soluble modulin alpha (psmα) virulence pathway is a master regulatory circuit that controls the transition of the bacterium from a colonizing to an invasive phenotype (Novick et al., 1993, NIH; Ji et al., 1995, NIH). This quorum-sensing system is mediated by the agr locus, which produces autoinducing peptides (AIPs) that activate the AgrC sensor kinase and its cognate response regulator, AgrA (Novick, 2003, Wikipedia). Once activated, AgrA directly induces the expression of the psmα operon, which encodes highly cytolytic peptides (PSMα1–4) capable of lysing human neutrophils and other host cells (Wang et al., 2007, NIH; Peschel and Otto, 2013, NIH). Additionally, the pathway triggers the production of RNAIII, a regulatory RNA that upregulates numerous toxins while downregulating surface adhesion proteins (Novick et al., 1993, NIH). Because of its central role in staphylococcal pathogenesis, particularly in community-acquired methicillin-resistant S. aureus (CA-MRSA), this pathway is a prime target for antivirulence therapies (Sully et al., 2014, NIH). Small molecules and peptides that inhibit AgrA DNA-binding or AgrC signaling are being developed to attenuate bacterial pathogenicity and facilitate immune clearance without directly killing the bacteria (Canovas et al., 2016, Frontiers; Daly et al., 2015, NIH). However, inhibition of the agr system can lead to increased biofilm formation, which presents a therapeutic challenge in chronic infections (Novick, 2003, Wikipedia).

Other names

Staphylococcus aureus agr systemAgr quorum sensing systemAgr-regulated virulence pathwayPSM alpha pathwayAccessory gene regulator pathway

Inhibition of AgrA DNA-binding, antagonism of the AgrC histidine kinase receptor, suppression of RNAIII transcription, and direct inhibition of phenol-soluble modulin (PSM) production.