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Journal of Bacteriology, June 2008, p. 4360-4366, Vol. 190, No. 12
0021-9193/08/$08.00+0     doi:10.1128/JB.00239-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Peptidoglycan of Stationary-Phase Mycobacterium tuberculosis Predominantly Contains Cross-Links Generated by L,D-Transpeptidation{triangledown}

Marie Lavollay,1,2,3 Michel Arthur,1,2,3 Martine Fourgeaud,1,2,3 Lionel Dubost,4,5 Arul Marie,4,5 Nicolas Veziris,6,7,8 Didier Blanot,9 Laurent Gutmann,1,2,3,10 and Jean-Luc Mainardi1,2,3,10*

INSERM, U872, LRMA, Equipe 12, F-75006 Paris, France,1 Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 872, F-75006 Paris, France,2 Université Paris Descartes, UMR S 872, Paris F-75006, France,3 Muséum National d'Histoire Naturelle, USM0502, Plateforme de Spectrométrie de Masse et de Protéomique du Muséum, F-75005 Paris, France,4 CNRS, UMR8041, F-75005 Paris, France,5 UPMC Université Paris 06, EA 1541, Laboratoire de Bactériologie-Hygiène, F-75005 Paris, France,6 AP-HP, Hôpital Pitié-Salpêtrière, Laboratoire de Bactériologie-Hygiène, F-75013 Paris, France,7 Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux, F-75013 Paris, France,8 Laboratoire des Enveloppes Bactériennes et Antibiotiques, Institut de Biochimie et Biophysique Moléculaire et Cellulaire, UMR 8619 CNRS, Univ Paris-Sud, Bât. 430, 91405 Orsay Cedex, France,9 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015 Paris, France,10

Received 16 February 2008/ Accepted 30 March 2008

Our understanding of the mechanisms used by Mycobacterium tuberculosis to persist in a "dormant" state is essential to the development of therapies effective in sterilizing tissues. Gene expression profiling in model systems has revealed a complex adaptive response thought to endow M. tuberculosis with the capacity to survive several months of combinatorial antibiotic treatment. We show here that this adaptive response may involve remodeling of the peptidoglycan network by substitution of 4->3 cross-links generated by the D,D-transpeptidase activity of penicillin-binding proteins by 3->3 cross-links generated by a transpeptidase of L,D specificity. A candidate gene, previously shown to be upregulated upon nutrient starvation, was found to encode an L,D-transpeptidase active in the formation of 3->3 cross-links. The enzyme, LdtMt1, was inactivated by carbapenems, a class of β-lactam antibiotics that are poorly hydrolyzed by the M. tuberculosis β-lactamases. LdtMt1 and carbapenems may therefore represent a target and a drug family relevant to the eradication of persistent M. tuberculosis.

* Corresponding author. Mailing address: LRMA INSERM U872, Centre de Recherches Biomédicales des Cordeliers, Université Pierre et Marie Curie and Université Paris Descartes, 15 Rue de l'Ecole de Médecine, 75270 Paris Cedex 06, France. Phone: 33 1 42 34 68 63. Fax: 33 1 43 25 68 12. E-mail: jean-luc.mainardi{at}crc.jussieu.fr

{triangledown} Published ahead of print on 11 April 2008.

Journal of Bacteriology, June 2008, p. 4360-4366, Vol. 190, No. 12
0021-9193/08/$08.00+0     doi:10.1128/JB.00239-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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