The Agr Quorum Sensing System Represses Persister Formation through Regulation of Phenol Soluble Modulins in Staphylococcus aureus

Abstract

The opportunistic pathogen Staphylococcus aureus has become an increasing threat to public health. While the Agr quorum sensing (QS) system is a master regulator of S. aureus virulence, its dysfunction has been frequently reported to promote bacteremia and mortality in clinical infections. Here we show that the Agr system is involved in persister formation in S. aureus. Mutation of either agrCA or agrD but not RNAIII resulted in increased persister formation of stationary phase cultures. RNA-seq analysis showed that in stationary phase AgrCA/AgrD and RNAIII mutants showed consistent up-regulation of virulence associated genes (lip and splE, etc.) and down-regulation of metabolism genes (bioA and nanK, etc.). Meanwhile, though knockout of agrCA or agrD strongly repressed expression of phenol soluble modulin encoding genes psmα1-4, psmβ1-2 and phenol soluble modulins (PSM) transporter encoding genes in the pmt operon, mutation of RNAIII enhanced expression of the genes. We further found that knockout of psmα1-4 or psmβ1-2 augmented persister formation and that co-overexpression of PSMαs and PSMβs reversed the effects of AgrCA mutation on persister formation. We also detected the effects on persister formation by mutations of metabolism genes (arcA, hutU, narG, nanK, etc.) that are potentially regulated by Agr system. It was found that deletion of the ManNAc kinase encoding gene nanK decreased persister formation. Taken together, these results shed new light on the PSM dependent regulatory role of Agr system in persister formation and may have implications for clinical treatment of MRSA persistent infections.

Anti-biofilm Activity of Graphene Quantum Dots via Self-Assembly with Bacterial Amyloid Proteins

“…In addition, such supramolecular complexes may also interfere with QS due to increased concentration of PSM monomers/oligomers that are tightly regulated by the Agr QS system. 48,49 Considering the broader implications of this work, additional studies on the interaction between GQDs and amyloidforming peptides in other species (e.g., Escherichia coli and Pseudomonas spp) will provide new approaches and insights into the potential manipulation of microbial communities. Further engineering of GQDs for enhanced association with amyloid peptides may lead to diverse effects on a wide range of biological processes, biomolecular functions, and signaling pathways.…”

Increased resistance of a methicillin-resistant Staphylococcus aureus Δagr mutant with modified control in fatty acid metabolism

“…PSMs are recently discovered short α-helical amphipathic peptides that cause neutrophil lysis after phagocytosis (Chatterjee et al 2013;Otto 2014). In addition, PSMs have been shown to exert other functions, including acting as regulators in persister cells and biofilm formation (Periasamy et al 2012;Xu et al 2017). Following agr activation, PSMs are produced to develop the biofilm structure and disperse the biofilm by forming a complex with eDNA, extracellular polysaccharides, and proteins, or by taking advantage of its surfactant characteristics (Schilcher et al 2016).…”

Oxidative stress drives the selection of quorum sensing mutants in the Staphylococcus aureus population

“…They also interact with the producer's own membrane and promote the release of membrane vesicles from the cytoplasmic membrane via an increase in membrane fluidity (23,24). Recently, PSMs were also shown to reduce persister formation (25,26). The antibacterial effect of PSMs is further supported by the necessity for the producer to protect itself from PSMs by the specific PSM transporter (Pmt) export system (27).…”