期刊
AAPS JOURNAL
卷 20, 期 2, 页码 -出版社
SPRINGER
DOI: 10.1208/s12248-018-0193-x
关键词
beta-lactamase; D,D-transpeptidase; imipenem; L,D-transpeptidase; meropenem
资金
- FDA Commissioner Fellowship Program
The final step of peptidoglycan (PG) synthesis in all bacteria is the formation of cross-linkage between PG-stems. The cross-linking between amino acids in different PG chains gives the peptidoglycan cell wall a 3-dimensional structure and adds strength and rigidity to it. There are two distinct types of cross-linkages in bacterial cell walls. D, D-transpeptidase (D, D-TPs) generate the classical 4 -> 3 cross-linkages and the L, D-transpeptidase (L, D-TPs) generate the 3 -> 3 non-classical peptide cross-linkages. The present study is aimed at understanding the nature of drug resistance associated with L, D-TP and gaining insights for designing novel antibiotics against multi-drug resistant bacteria. Penicillin and cephalosporin classes of beta-lactams cannot inhibit L, D-TP function; however, carbapenems inactivate its function. We analyzed the structure of L, D-TP of Mycobacterium tuberculosis in the apo form and in complex with meropenem and imipenem. The periplasmic region of L, D-TP folds into three domains. The catalytic residues are situated in the C-terminal domain. The acylation reaction occurs between carbapenem antibiotics and the catalytic Cys-354 forming a covalent complex. This adduct formation mimics the acylation of L, D-TP with the donor PG-stem. A novel aspect of this study is that in the crystal structures of the apo and the carbapenem complexes, the N-terminal domain has a muropeptide unit non-covalently bound to it. Another interesting observation is that the calcium complex crystallized as a dimer through head and tail interactions between the monomers.
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