Structural Basis for the Interaction and Processing of β-Lactam Antibiotics by l,d-Transpeptidase 3 (Ldt Mt3 ) from Mycobacterium tuberculosis.
ACS infectious diseases(2019)
Abstract
Targeting Mycobacterium tuberculosis peptidoglycans with β-lactam antibiotics represents a strategy to address increasing resistance to anti-tubercular drugs. β-Lactams inhibit peptidoglycan synthases such as L,D-transpeptidases, a group of carbapenem-sensitive enzymes that stabilize peptidoglycans through 3→3 cross-links. M. tuberculosis encodes five L,D-transpeptidases (LdtMt1-5) of which LdtMt3 is one of the less understood. Herein, we structurally characterized the apo and faropenem-acylated forms of LdtMt3 at 1.3 and 1.8 Å resolution, respectively. These structures revealed a fold and catalytic diad similar to those of other LdtsMt enzymes, supporting its involvement in transpeptidation reactions despite divergences in active site size and charges. The LdtMt3-faropenem structure indicated that faropenem is degraded after Cys-246 acylation and possibly only a β-OH-butyrate or an acetyl group (C2H3O) covalently attached to the enzyme remains, an observation that strongly supports the notion that LdtMt3 is inactivated by β-lactams. Docking simulations with intact β-lactams predicted key LdtMt3 residues that interact with these antibiotics. We also characterized the heat of acylation involved in the binding and reaction of LdtMt3 for ten β-lactams belonging to four different classes and imipenem had the highest inactivation constant. This work provides key insights into the structure, binding mechanisms, and degradation of β-lactams by LdtMt3 which may be useful for the development of additional β-lactams with potential anti-tubercular activity.
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Key words
Mycobacterium tuberculosis,L,D-transpeptidase,beta-lactam antibiotics,faropenem,X-ray structure,multidrug resistance
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