Structural basis for the inhibition of Mycobacterium tuberculosis L, D‐transpeptidase by meropenem, a drug effective against extensively drug‐resistant strains. (24th March 2013)

• Record Type: Journal Article
• Authors: Kim, Hyoun Sook; Kim, Jieun; Im, Ha Na; Yoon, Ji Young; An, Doo Ri; Yoon, Hye Jin; Kim, Jin Young; Min, Hye Kyeoung; Kim, Soon‐Jong; Lee, Jae Young; Han, Byung Woo; Suh, Se Won
• Is Part Of: Acta crystallographica. Volume 69:Part 3(2013:Mar.)
• Page Start: 420
• Page End: 431
• Publication Date: 2013-03-24
• Subjects: Biomolecules -- Structure -- Periodicals; Physical biochemistry -- Periodicals; X-ray crystallography -- Periodicals; Crystallography -- Periodicals; 572
• DOI: 10.1107/S0907444912048998
• Languages: English
• ISSNs: 0907-4449

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Difficulty in the treatment of tuberculosis and growing drug resistance in <italic>Mycobacterium tuberculosis</italic> (<italic>Mtb</italic>) are a global health issue. Carbapenems inactivate L, D‐transpeptidases; meropenem, when administered with clavulanate, showed <italic>in vivo</italic> activity against extensively drug‐resistant <italic>Mtb</italic> strains. Ldt<sub>Mt2</sub> (Rv2518c), one of two functional L, D‐transpeptidases in <italic>Mtb</italic>, is predominantly expressed over Ldt<sub>Mt1</sub> (Rv0116c). Here, the crystal structure of N‐terminally truncated Ldt<sub>Mt2</sub> (residues Leu131–Ala408) is reported in both ligand‐free and meropenem‐bound forms. The structure of meropenem‐inhibited Ldt<sub>Mt2</sub> provides a detailed structural view of the interactions between a carbapenem drug and <italic>Mtb</italic> L, D‐transpeptidase. The structures revealed that the catalytic L, D‐transpeptidase domain of Ldt<sub>Mt2</sub> 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 Ldt<sub>Mt2</sub>. 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 <italic>via</italic> three narrow paths. This work will facilitate structure‐guided discovery of L, D‐transpeptidase inhibitors as novel antituberculosis drugs against drug‐resistant <italic>Mtb</italic>.</p> </abstract>