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Crystal structure of the transpeptidase LdtMt2 from Mycobacterium tuberculosis in complex with cyanamide analogue 31
Structural highlights
FunctionLDT2_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 PubMedDisruption of bacterial cell wall biosynthesis in Mycobacterium tuberculosis is a promising target for treating tuberculosis. The l,d-transpeptidase Ldt(Mt2), which is responsible for the formation of 3 --> 3 cross-links in the cell wall peptidoglycan, has been identified as essential for M. tuberculosis virulence. We optimised a high-throughput assay for Ldt(Mt2), and screened a targeted library of approximately 10 000 electrophilic compounds. Potent inhibitor classes were identified, including established (e.g., beta-lactams) and unexplored covalently reacting electrophilic groups (e.g., cyanamides). Protein-observed mass spectrometric studies reveal most classes to react covalently and irreversibly with the Ldt(Mt2) catalytic cysteine (Cys354). Crystallographic analyses of seven representative inhibitors reveal induced fit involving a loop enclosing the Ldt(Mt2) active site. Several of the identified compounds have a bactericidal effect on M. tuberculosis within macrophages, one with an MIC(50) value of approximately 1 muM. The results provide leads for the development of new covalently reaction inhibitors of Ldt(Mt2) and other nucleophilic cysteine enzymes. High-throughput screen with the l,d-transpeptidase Ldt(Mt2) of Mycobacterium tuberculosis reveals novel classes of covalently reacting inhibitors.,de Munnik M, Lang PA, De Dios Anton F, Cacho M, Bates RH, Brem J, Rodriguez Miquel B, Schofield CJ Chem Sci. 2023 May 30;14(26):7262-7278. doi: 10.1039/d2sc06858c. eCollection 2023 , Jul 5. PMID:37416715[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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