The peptidoglycan of stationary-phase Mycobacterium tuberculosis predominantly contains cross-links generated by L,D-transpeptidation.
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.
Lavollay
Marie
M
INSERM, U872, LRMA, Equipe 12, F-75006 Paris, France.
Arthur
Michel
M
Fourgeaud
Martine
M
Dubost
Lionel
L
Marie
Arul
A
Veziris
Nicolas
N
Blanot
Didier
D
Gutmann
Laurent
L
Mainardi
Jean-Luc
JL
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
D000900:Anti-Bacterial Agents; D010457:Peptidoglycan; D047090:beta-Lactams; D010458:Peptidyl Transferases