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N-Acylhomoserine Lactones Antagonize Virulence Gene Expression and Quorum Sensing in Staphylococcus aureus

Saara Qazi,^1, Barry Middleton,^1,, Siti Hanna Muharram,¹ Alan Cockayne,¹ Philip Hill,^1,3 Paul O'Shea,² Siri Ram Chhabra,¹ Miguel Cámara,¹ and Paul Williams^1*

Institute of Infection, Immunity and Inflammation, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD,¹ School of Biology, University of Nottingham, Nottingham NG7 2RD,² School of Biosciences, Sutton Bonington Campus, University of Nottingham, Loughborough, Leicestershire LE12 5RD, United Kingdom³

Received 9 June 2005/ Returned for modification 14 July 2005/ Accepted 24 October 2005

Many gram-negative bacteria employ N-acylhomoserine lactone (AHL)-mediated quorum sensing to control virulence. To determine whether gram-positive bacteria such as Staphylococcus aureus respond to AHLs, we used a growth-dependent lux reporter fusion. Exposure of S. aureus to different AHLs revealed that 3-oxo-substituted AHLs with C₁₀ to C₁₄ acyl chains inhibited light output and growth in a concentration-dependent manner, while short-chain AHLs had no effect. N-(3-Oxododecanoyl)-L-homoserine lactone (3-oxo-C₁₂-HSL) inhibited the production of exotoxins and cell wall fibronectin-binding proteins but enhanced protein A expression. Since these processes are reciprocally regulated via the S. aureus agr quorum-sensing system, which in turn, is regulated via sar, we examined the effect of AHLs on sarA and agr. At sub-growth-inhibitory concentrations of 3-oxo-C₁₂-HSL, both sarA expression and agr expression were inhibited, indicating that the action of 3-oxo-C₁₂-HSL is mediated at least in part through antagonism of quorum sensing in S. aureus. Spent culture supernatants from Pseudomonas aeruginosa, which produces both 3-oxo-C₁₂-HSL and N-butanoyl-homoserine lactone (C₄-HSL), also inhibited agr expression, although C₄-HSL itself was inactive in this assay. Since quorum sensing in S. aureus depends on the activities of membrane-associated proteins, such as AgrB, AgrC, and AgrD, we investigated whether AHLs perturbed S. aureus membrane functionality by determining their influence on the membrane dipole potential. From the binding curves obtained, a dissociation constant of 7 µM was obtained for 3-oxo-C₁₂-HSL, indicating the presence of a specific saturable receptor, whereas no binding was observed for C₄-HSL. These data demonstrate that long-chain 3-oxo-substituted AHLs, such as 3-oxo-C₁₂-HSL, are capable of interacting with the S. aureus cytoplasmic membrane in a saturable, specific manner and at sub-growth-inhibitory concentrations, down-regulating exotoxin production and both sarA and agr expression.

Editor: J. B. Bliska

S.Q. and B.M. made equal contributions to this work.

Present address: ITI Life Sciences, Innovation House, 17 Luna Place, Dundee Technology Park, Dundee DD2 1TP, United Kingdom.

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