Abstract
Difficulty in the treatment of tuberculosis and growing drug resistance in Mycobacterium tuberculosis (Mtb) are a global health issue. Carbapenems inactivate l,d-transpeptidases; meropenem, when administered with clavulanate, showed in vivo activity against extensively drug-resistant Mtb strains. LdtMt2 (Rv2518c), one of two functional l,d-transpeptidases in Mtb, is predominantly expressed over LdtMt1 (Rv0116c). Here, the crystal structure of N-terminally truncated LdtMt2 (residues Leu131-Ala408) is reported in both ligand-free and meropenem-bound forms. The structure of meropenem-inhibited LdtMt2 provides a detailed structural view of the interactions between a carbapenem drug and Mtb l,d-transpeptidase. The structures revealed that the catalytic l,d-transpeptidase domain of LdtMt2 is preceded by a bacterial immunogloblin-like Big-5 domain and is followed by an extended C-terminal tail that interacts with both domains. Furthermore, it is shown using mass analyses that meropenem acts as a suicide inhibitor of LdtMt2. Upon acylation of the catalytic Cys354 by meropenem, the 'active-site lid' undergoes a large conformational change to partially cover the active site so that the bound meropenem is accessible to the bulk solvent via three narrow paths. This work will facilitate structure-guided discovery of l,d-transpeptidase inhibitors as novel antituberculosis drugs against drug-resistant Mtb.
Original language | English |
---|---|
Pages (from-to) | 420-431 |
Number of pages | 12 |
Journal | Acta Crystallographica Section D: Biological Crystallography |
Volume | 69 |
Issue number | 3 |
DOIs | |
State | Published - Mar 2013 |
Keywords
- antituberculosis drug discovery
- carbapenem
- l,d-transpeptidases
- Ldt
- meropenem
- Mt2594
- Mycobacterium tuberculosis
- peptidoglycans
- Rv2518c