7A1C

LdtMT2 with covalent adduct derived from N-Thio-beta-lactam 1a

7A1C の概要

• エントリーDOI: 10.2210/pdb7a1c/pdb
• 関連するPDBエントリー: 7A0Z 7A10 7A11
• 分子名称: L,D-transpeptidase 2, DIMETHYL SULFOXIDE (3 entities in total)
• 機能のキーワード: transpeptidase, cell wall, peptidoglycan, antibiotic, beta-lactam, covalent inhibitor, mycobacterium tuberculosis, ligase
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 57201.71

構造登録者

Schnell, R.,Steiner, E.M. (登録日: 2020-08-12, 公開日: 2021-04-21, 最終更新日: 2024-01-31)

主引用文献

Martelli, G.,Pessatti, T.B.,Steiner, E.M.,Cirillo, M.,Caso, C.,Bisognin, F.,Landreh, M.,Monte, P.D.,Giacomini, D.,Schnell, R.
N-Thio-beta-lactams targeting L,D-transpeptidase-2, with activity against drug-resistant strains of Mycobacterium tuberculosis.
Cell Chem Biol, 28:1321-, 2021

PubMed Abstract: Effective treatment of tuberculosis is frequently hindered by the emerging antimicrobial resistance of Mycobacterium tuberculosis. The present study evaluates monocyclic β-lactam compounds targeting the mycobacterial cell wall remodeling. Novel N-thio-β-lactams were designed, synthesized, and characterized on the L,D-transpeptidase-2, a validated target in M. tuberculosis. The candidates were evaluated in biochemical assays identifying five compounds presenting target-specific kinetic constants equal or superior to meropenem, a carbapenem currently considered for tuberculosis therapy. Mass spectrometry in line with the crystal structures of five target-ligand complexes revealed that the N-thio-β-lactams act via an unconventional mode of adduct formation, transferring the thio-residues from the lactam ring to the active-site cysteine of Ldt. The resulting stable adducts lead to a long-term inactivation of the target protein. Finally, the candidates were evaluated in vitro against a drug-susceptible and multidrug-resistant clinical isolates of M. tuberculosis, confirming the antimycobacterial effect of these novel compounds.

PubMed: 33826941
DOI: 10.1016/j.chembiol.2021.03.008

実験手法

X-RAY DIFFRACTION (1.77 Å)