Structural basis for the inhibition of Mycobacterium tuberculosis l,d-transpeptidase by meropenem, a drug effective against extensively drug-resistant strains

Hyoun Sook Kim, Jieun Kim, Ha Na Im, Ji Young Yoon, Doo Ri An, Hye Jin Yoon, Jin Young Kim, Hye Kyeoung Min, Soon Jong Kim, Jae Young Lee, Byung Woo Han, Se Won Suh

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71 Scopus citations

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 languageEnglish
Pages (from-to)420-431
Number of pages12
JournalActa Crystallographica Section D: Biological Crystallography
Volume69
Issue number3
DOIs
StatePublished - Mar 2013

Keywords

  • antituberculosis drug discovery
  • carbapenem
  • l,d-transpeptidases
  • Ldt
  • meropenem
  • Mt2594
  • Mycobacterium tuberculosis
  • peptidoglycans
  • Rv2518c

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