7A10
LppS with covalent adduct derived from 1g
Summary for 7A10
| Entry DOI | 10.2210/pdb7a10/pdb |
| Related | 7A0Z |
| Descriptor | L,D-transpeptidase 2, 4-methoxycyclohexa-2,5-diene-1-thione (3 entities in total) |
| Functional Keywords | transpeptidase, cell wall, peptidoglycan, antibiotic, beta-lactam, covalent inhibitor, mycobacterium tuberculosis, ligase |
| Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
| Total number of polymer chains | 2 |
| Total formula weight | 57301.73 |
| Authors | Schnell, R.,Steiner, E.M. (deposition date: 2020-08-11, release date: 2021-04-21, Last modification date: 2024-10-23) |
| Primary citation | 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 Cited by 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: 33826941DOI: 10.1016/j.chembiol.2021.03.008 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.85 Å) |
Structure validation
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