The Library
Structural basis for the interaction and processing of β-Lactam antibiotics by l,d-transpeptidase 3 (LdtMt3) from mycobacterium tuberculosis
Tools
Tools
Tools
Libreros-Zúñiga, Gerardo Andrés, dos Santos Silva, Catharina, Salgado Ferreira, Rafaela and Dias, Marcio Vinicius Bertacine (2019) Structural basis for the interaction and processing of β-Lactam antibiotics by l,d-transpeptidase 3 (LdtMt3) from mycobacterium tuberculosis. ACS Infectious Diseases, 5 (2). pp. 260-271. doi:10.1021/acsinfecdis.8b00244 ISSN 2373-8227.
Research output not available from this repository.
Request-a-Copy directly from author or use local Library Get it For Me service.
Official URL: http://dx.doi.org/10.1021/acsinfecdis.8b00244
Abstract
Targeting Mycobacterium tuberculosis peptidoglycans with β-lactam antibiotics represents a strategy to address increasing resistance to antitubercular 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 antitubercular activity.
| Item Type: | Journal Article | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||
| Journal or Publication Title: | ACS Infectious Diseases | ||||||||
| Publisher: | American Chemical Society (ACS) | ||||||||
| ISSN: | 2373-8227 | ||||||||
| Official Date: | 8 February 2019 | ||||||||
| Dates: |
|
||||||||
| Volume: | 5 | ||||||||
| Number: | 2 | ||||||||
| Page Range: | pp. 260-271 | ||||||||
| DOI: | 10.1021/acsinfecdis.8b00244 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Restricted or Subscription Access |
Request changes or add full text files to a record
Repository staff actions (login required)
 |
View Item |
