AUTHOR=Xu Tao , Wang Xu-Yang , Cui Peng , Zhang Yu-Meng , Zhang Wen-Hong , Zhang Ying 

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

JOURNAL=Frontiers in Microbiology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2017.02189

DOI=10.3389/fmicb.2017.02189

ISSN=1664-302X

ABSTRACT=<p>The opportunistic pathogen <italic>Staphylococcus aureus</italic> has become an increasing threat to public health. While the Agr quorum sensing (QS) system is a master regulator of <italic>S. aureus</italic> 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 <italic>S. aureus</italic>. Mutation of either <italic>agrCA</italic> or <italic>agrD</italic> but not <italic>RNAIII</italic> 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 (<italic>lip</italic> and <italic>splE</italic>, etc.) and down-regulation of metabolism genes (<italic>bioA</italic> and <italic>nanK</italic>, etc.). Meanwhile, though knockout of <italic>agrCA</italic> or <italic>agrD</italic> strongly repressed expression of phenol soluble modulin encoding genes <italic>psmα1-4</italic>, <italic>psm</italic>β<italic>1-2</italic> and phenol soluble modulins (PSM) transporter encoding genes in the <italic>pmt</italic> operon, mutation of RNAIII enhanced expression of the genes. We further found that knockout of <italic>psmα1-4</italic> or <italic>psm</italic>β<italic>1-2</italic> 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 (<italic>arcA</italic>, <italic>hutU</italic>, <italic>narG</italic>, nanK, etc.) that are potentially regulated by Agr system. It was found that deletion of the ManNAc kinase encoding gene <italic>nanK</italic> 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.</p>