title: The peptidoglycan of stationary-phase Mycobacterium tuberculosis predominantly contains cross-links generated by L,D-transpeptidation.
abstract: 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, Ldt(Mt1), was inactivated by carbapenems, a class of beta-lactam antibiotics that are poorly hydrolyzed by the M. tuberculosis beta-lactamases. Ldt(Mt1) and carbapenems may therefore represent a target and a drug family relevant to the eradication of persistent M. tuberculosis.
authors.affiliation: INSERM, U872, LRMA, Equipe 12, F-75006 Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Lavollay
authors.forename: Michel
authors.initials: M
authors.lastname: Arthur
authors.forename: Martine
authors.initials: M
authors.lastname: Fourgeaud
authors.forename: Lionel
authors.initials: L
authors.lastname: Dubost
authors.forename: Arul
authors.initials: A
authors.lastname: Marie
authors.forename: Nicolas
authors.initials: N
authors.lastname: Veziris
authors.forename: Didier
authors.initials: D
authors.lastname: Blanot
authors.forename: Laurent
authors.initials: L
authors.lastname: Gutmann
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Mainardi
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D010457:Peptidoglycan / Q000378:metabolism*; D010458:Peptidyl Transferases / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D010457:Peptidoglycan; D047090:beta-Lactams; D010458:Peptidyl Transferases