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JAC Advance Access originally published online on February 8, 2007
Journal of Antimicrobial Chemotherapy 2007 59(3):370-377; doi:10.1093/jac/dkl507
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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

Molecular basis of Tropheryma whipplei doxycycline susceptibility examined by transcriptional profiling

My Van La1, Pascal Barbry2,3, Didier Raoult1 and Patricia Renesto1,*

1 Unité des Rickettsies, CNRS-UMR6020, IFR48, Faculté de Médecine, 27 Bd Jean Moulin, Marseille, F13385, France 2 CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097, Sophia Antipolis, F06560, France 3 Université de Nice Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097, Sophia Antipolis, F06560, France

Received 19 October 2006; returned 11 November 2006; revised 21 November 2006; accepted 21 November 2006

* Corresponding author. Tel: +33-491-32-43-75; Fax: +33-491-38-77-72; E-mail: patricia.renesto{at}medecine.univ-mrs.fr

Objectives and methods: Tropheryma whipplei is a poorly studied bacterium responsible for Whipple's disease. In this study, its susceptibility to doxycycline was investigated at a transcriptional level using a whole-genome DNA microarray.

Results: Exposure of T. whipplei to the MIC of doxycycline (0.5 mg/L) induced antibiotic-specific primary expression profiles, while indirect effects were detected at 10 x MIC. In contrast to what was observed for several microorganisms exposed to antibiotics, the heat-shock proteins were not affected. Consistent with the mode of action of this translation inhibitor, genes encoding for ribosomal proteins and translation factors were differentially transcribed. This analysis also evidenced the regulation of genes that should account for cell growth arrest. Long-term survival of non-replicating bacteria is likely to be ensured by an increased level of ppGpp, the nucleotide effector of the stringent response. The gene expression profile observed with 10 x MIC was mainly characterized by the up-regulation of ABC transporters that possibly form efflux and detoxification systems, through which T. whipplei may limit the effects of this bacteriostatic compound. Obtained microarray data showed good agreement with real-time quantitative PCR (R2 = 0.969).

Conclusions: This work represents the first comprehensive genomic approach providing insights into the expression signature triggered by the exposure of T. whipplei to antibiotics.

Keywords: antibiotics , transcription , efflux pumps , microarrays


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