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 imipenemin-activated 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.