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Infection and Immunity, October 2002, p. 5635-5646, Vol. 70, No. 10
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.10.5635-5646.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

N-Acylhomoserine Lactones Undergo Lactonolysis in a pH-, Temperature-, and Acyl Chain Length-Dependent Manner during Growth of Yersinia pseudotuberculosis and Pseudomonas aeruginosa

Edwin A. Yates,1 Bodo Philipp,2,3,{dagger} Catherine Buckley,2,3 Steve Atkinson,2,3 Siri Ram Chhabra,3 R. Elizabeth Sockett,4 Morris Goldner,5 Yves Dessaux,6 Miguel Cámara,2,3 Harry Smith,7 and Paul Williams2,3*

School of Biosciences,1 Medical School, University of Birmingham, Birmingham B15 2TT,7 Institute of Infections and Immunity,2 Institute of Genetics, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH,4 School of Pharmaceutical Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom,3 Faculté de Médécine, Université Laval, Cité Universitaire, Québec G1K 7P4, Canada,5 Institut des Sciences du Végétal, CNRS UPR2235 Gif-sur-Yvette Cedex, France6

Received 7 March 2002/ Returned for modification 30 April 2002/ Accepted 8 July 2002

In gram-negative bacterial pathogens, such as Pseudomonas aeruginosa and Yersinia pseudotuberculosis, cell-to-cell communication via the N-acylhomoserine lactone (AHL) signal molecules is involved in the cell population density-dependent control of genes associated with virulence. This phenomenon, termed quorum sensing, relies upon the accumulation of AHLs to a threshold concentration at which target structural genes are activated. By using biosensors capable of detecting a range of AHLs we observed that, in cultures of Y. pseudotuberculosis and P. aeruginosa, AHLs accumulate during the exponential phase but largely disappear during the stationary phase. When added to late-stationary-phase, cell-free culture supernatants of the respective pathogen, the major P. aeruginosa [N-butanoylhomoserine lactone (C4-HSL) and N-(3-oxododecanoyl)homoserine lactone (3-oxo-C12-HSL)] and Y. pseudotuberculosis [N-(3-oxohexanoyl)homoserine lactone (3-oxo-C6-HSL) and N-hexanoylhomoserine lactone (C6-HSL)] AHLs were inactivated. Short-acyl-chain compounds (e.g., C4-HSL) were turned over more extensively than long-chain molecules (e.g., 3-oxo-C12-HSL). Little AHL inactivation occurred with cell extracts, and no evidence for inactivation by specific enzymes was apparent. This AHL turnover was discovered to be due to pH-dependent lactonolysis. By acidifying the growth media to pH 2.0, lactonolysis could be reversed. By using carbon-13 nuclear magnetic resonance spectroscopy, we found that the ring opening of homoserine lactone (HSL), N-propionyl HSL (C3-HSL), and C4-HSL increased as pH increased but diminished as the N-acyl chain was lengthened. At low pH levels, the lactone rings closed but not via a simple reversal of the ring opening reaction mechanism. Ring opening of C4-HSL, C6-HSL, 3-oxo-C6-HSL, and N-octanoylhomoserine lactone (C8-HSL), as determined by the reduction of pH in aqueous solutions with time, was also less rapid for AHLs with more electron-donating longer side chains. Raising the temperature from 22 to 37°C increased the rate of ring opening. Taken together, these data show that (i) to be functional under physiological conditions in mammalian tissue fluids, AHLs require an N-acyl side chain of at least four carbons in length and (ii) that the longer the acyl side chain the more stable the AHL signal molecule.

* Corresponding author. Mailing address: Institute of Infections and Immunity, University of Nottingham, Queen's Medical Centre Nottingham NG7 2UH, United Kingdom. Phone: 44-115-951-5047. Fax: 44-115-846-6296. E-mail: paul.williams{at}nottingham.ac.uk.

Editor: A. D. O'Brien

{dagger} Present address: Microbial Ecology, University of Konstanz, 78457 Konstanz, Germany.

Infection and Immunity, October 2002, p. 5635-5646, Vol. 70, No. 10
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.10.5635-5646.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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