Structures of free and inhibited forms of the L,D-­transpeptidase Ldt_Mt1 from Mycobacterium tuberculosis

The modelling of peptidoglycan is responsible for key cellular processes in Mycobacterium tuberculosis such as cell growth, division and resuscitation from dormancy. The structure of M. tuberculosis peptidoglycan is atypical since it contains a majority of 3,3 cross-links synthesized by L,D-transpeptidases that replace the 4,3 cross-links formed by the D,D-transpeptidase activity of classical penicillin-binding proteins. Carba­penems inactivate these L,D-transpeptidases and in combination with clavulanic acid are bactericidal against extensively drug-­resistant M. tuberculosis. Here, crystal structures of the L,D-­transpeptidase Ldt_Mt1 from M. tuber­culosis in a ligand-free form and in complex with the carbapenem imipenem are reported. Elucidation of the structural features of Ldt_Mt1 unveils analogies and differences between the two key transpeptidases of M. tuberculosis: Ldt_Mt1 and Ldt_Mt2. In addition, the structure of imipenem-inactivated Ldt_Mt1 provides a detailed structural view of the interactions between a carbapenem drug and Ldt_Mt1. By providing the key interactions in the binding of carbapenem to Ldt_Mt1, this work will facilitate structure-guided discovery of L,D-transpeptidase inhibitors as novel antitubercular agents against drug-resistant M. tuberculosis.