7a1c
From Proteopedia
LdtMT2 with covalent adduct derived from N-Thio-beta-lactam 1a
Structural highlights
Function[LDT2_MYCTU] Generates 3->3 cross-links in peptidoglycan, catalyzing the cleavage of the mDap(3)-D-Ala(4) bond of a tetrapeptide donor stem and the formation of a bond between the carbonyl of mDap(3) of the donor stem and the side chain of mDap(3) of the acceptor stem. Is specific for donor substrates containing a stem tetrapeptide since it cannot use pentapeptide stems.[1] Publication Abstract from PubMedEffective treatment of tuberculosis is frequently hindered by the emerging antimicrobial resistance of Mycobacterium tuberculosis. The present study evaluates monocyclic beta-lactam compounds targeting the mycobacterial cell wall remodeling. Novel N-thio-beta-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-beta-lactams act via an unconventional mode of adduct formation, transferring the thio-residues from the lactam ring to the active-site cysteine of LdtMt2. 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. N-Thio-beta-lactams targeting L,D-transpeptidase-2, with activity against drug-resistant strains of Mycobacterium tuberculosis.,Martelli G, Pessatti TB, Steiner EM, Cirillo M, Caso C, Bisognin F, Landreh M, Monte PD, Giacomini D, Schnell R Cell Chem Biol. 2021 Mar 30. pii: S2451-9456(21)00147-1. doi:, 10.1016/j.chembiol.2021.03.008. PMID:33826941[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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