biostudies-literatureAntypas HMOH | National Medical Research CouncilMinistry of Education - Singapore (MOE)Swiss National Science FoundationMOH | National Medical Research Council (NMRC)Ministry of Education - Singapore1668https://www.ebi.ac.uk/biostudies/studies/S-EPMC12909850biostudies-literatureUnknown17(1)Infective endocarditis (IE) is a severe heart infection caused predominantly by Gram-positive bacteria forming biofilm on heart valves. While biofilm formation is central to disease progression, the underlying bacterial mechanisms remain poorly understood. Here, we identify the Fsr quorum sensing (QS) system of Enterococcus faecalis as an unexpected negative regulator of biofilm and pathogenesis in IE. Using microfluidic and in vivo models, we show that blood flow prevents Fsr activation in early IE, with Fsr induction occurring only later, once bacteria form biofilm microcolonies and become shielded from flow. Deletion of Fsr promotes robust biofilm growth, driven partly through the downregulation of GelE and SprE proteases, reprograms metabolism by upregulating lrgAB to enhance pyruvate Nature communicationsLoss of Fsr quorum sensing promotes biofilm formation and worsens outcomes in enterococcal infective endocarditis.PMC12909850204343211422MOH-000645310030MOE2019-T2-2-089Schutz SDNeo CJYMuthualagu Natarajan LKloehn JBrugger SDSchmidtchen VZinkernagel ASNg KKFWong JJManzano CVan Tyne DColomer-Winter CWong SLTan RJWYanhong LITanoto FRKline KAPethe KRadhesh SMAntypas HStaiger WIda Silva RAGHasse BfalseLoss of Fsr quorum sensing promotes biofilm formation and worsens outcomes in enterococcal infective endocarditis.Infective endocarditis (IE) is a severe heart infection caused predominantly by Gram-positive bacteria forming biofilm on heart valves. While biofilm formation is central to disease progression, the underlying bacterial mechanisms remain poorly understood. Here, we identify the Fsr quorum sensing (QS) system of Enterococcus faecalis as an unexpected negative regulator of biofilm and pathogenesis in IE. Using microfluidic and in vivo models, we show that blood flow prevents Fsr activation in early IE, with Fsr induction occurring only later, once bacteria form biofilm microcolonies and become shielded from flow. Deletion of Fsr promotes robust biofilm growth, driven partly through the downregulation of GelE and SprE proteases, reprograms metabolism by upregulating lrgAB to enhance pyruvate 2026-01-01T00:00:00Z2026 Jan2026-07-16T18:03:03.348Z2026-07-09T11:10:41.198ZS-EPMC129098504153529910.1038/s41467-026-68366-8