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JAC Advance Access originally published online on February 27, 2007
Journal of Antimicrobial Chemotherapy 2007 59(4):607-615; doi:10.1093/jac/dkm021
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Loss of penicillin tolerance by inactivating the carbon catabolite repression determinant CcpA in Streptococcus gordonii

A. Bizzini, J. M. Entenza and P. Moreillon*

Faculty of Biology and Medicine, Department of Fundamental Microbiology, Biophore Building, University of Lausanne, 1015 Lausanne, Switzerland

Received 18 August 2006; returned 20 October 2006; revised 15 January 2007; accepted 17 January 2007

* Corresponding author. Tel: +41-21-692-5600; Fax: +41-21-692-5605; E-mail: philippe.moreillon{at}unil.ch

Objectives: Antibiotic tolerance is a phenomenon allowing bacteria to withstand drug-induced killing. Here, we studied a penicillin-tolerant mutant of Streptococcus gordonii (Tol1), which was shown to be deregulated in the expression of the arginine deiminase operon (arc). arc was not directly responsible for tolerance, but is controlled by the global regulator CcpA. Therefore, we sought whether CcpA might be implicated in tolerance.

Methods: The ccpA gene was characterized and subsequently inactivated by PCR ligation mutagenesis in both the susceptible wild-type (WT) and Tol1. The minimal inhibitory concentration and time–kill curves for the strains were determined and the outcome of penicillin treatment in experimental endocarditis assessed.

Results: ccpA sequence and expression were similar between the WT and Tol1 strains. In killing assays, the WT lost 3.5 ± 0.6 and 5.3 ± 0.6 log10 cfu/mL and Tol1 lost 0.4 ± 0.2 and 1.4 ± 0.9 log10 cfu/mL after 24 and 48 h of penicillin exposure, respectively. Deletion of ccpA almost totally restored Tol1 kill susceptibility (loss of 2.5 ± 0.7 and 4.9 ± 0.7 log10 cfu/mL at the same endpoints). In experimental endocarditis, penicillin treatment induced a significant reduction in vegetation bacterial densities between Tol1 (4.1 log10 cfu/g) and Tol1{Delta}ccpA (2.4 log10 cfu/g). Restitution of ccpA re-established the tolerant phenotype both in vitro and in vivo.

Conclusions: CcpA, a global regulator of the carbon catabolite repression system, is implicated in penicillin tolerance both in vitro and in vivo. This links antibiotic survival to bacterial sugar metabolism. However, since ccpA sequence and expression were similar between the WT and Tol1 strains, other factors are probably involved in tolerance.

Keywords: experimental endocarditis , antibiotics , arginine deiminase


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