Lavollay Marie, Arthur Michel, Fourgeaud Martine, Dubost Lionel, Marie Arul, Veziris Nicolas, Blanot Didier, Gutmann Laurent, Mainardi Jean-Luc
INSERM, U872, LRMA, Equipe 12, F-75006 Paris, France.
J Bacteriol. 2008 Jun;190(12):4360-6. doi: 10.1128/JB.00239-08. Epub 2008 Apr 11.
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.
我们对结核分枝杆菌在“休眠”状态下持续存在所使用机制的理解，对于开发能够有效清除组织中细菌的疗法至关重要。模型系统中的基因表达谱分析揭示了一种复杂的适应性反应，这种反应被认为赋予结核分枝杆菌在联合抗生素治疗数月后仍能存活的能力。我们在此表明，这种适应性反应可能涉及肽聚糖网络的重塑，即由青霉素结合蛋白的D，D - 转肽酶活性产生的4→3交联被L，D特异性转肽酶产生的3→3交联所取代。一个先前显示在营养饥饿时上调的候选基因，被发现编码一种在形成3→3交联中具有活性的L，D - 转肽酶。该酶Ldt（Mt1）被碳青霉烯类药物灭活，碳青霉烯类是一类β - 内酰胺抗生素，结核分枝杆菌β - 内酰胺酶对其水解作用较弱。因此，Ldt（Mt1）和碳青霉烯类药物可能分别代表与根除持续存在的结核分枝杆菌相关的一个靶点和一类药物。
