Advanced search
Start date
Betweenand
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Structural Basis for the Interaction and Processing of beta-Lactam Antibiotics by L,D-Transpeptidase 3 (Ldt(Mt3)) from Mycobacterium tuberculosis

Full text
Author(s):
Libreros-Zuniga, Gerardo Andres [1, 2, 3] ; Silva, Catharina dos Santos [1] ; Ferreira, Rafaela Salgado [4] ; Bertacine Dias, Marcio Vinicius [1, 2]
Total Authors: 4
Affiliation:
[1] Univ Sao Paulo, Dept Microbiol, Inst Ciencias Biomed, Ave Prof Lineu Prestes, BR-1374 Sao Paulo - Brazil
[2] Univ Estadual Paulista, Inst Biociencias Letras & Ciencias Exatas, Rua Cristrivao Colombo, BR-2265 Sao Jose Do Rio Preto - Brazil
[3] Univ Valle, Fac Salud, Dept Microbiol, Calle 4B 36-00, Cali - Colombia
[4] Univ Fed Minas Gerais, Dept Bioquim & Imunol, Inst Ciencias Biol, Ave Antonio Carlos, BR-6627 Belo Horizonte, MG - Brazil
Total Affiliations: 4
Document type: Journal article
Source: ACS INFECTIOUS DISEASES; v. 5, n. 2, p. 260-271, FEB 2019.
Web of Science Citations: 1
Abstract

Targeting Mycobacterium tuberculosis peptidoglycans with beta-lactam antibiotics represents a strategy to address increasing resistance to antitubercular drugs. beta-Lactams inhibit peptidoglycan synthases such as L,D-transpeptidases, a group of carbapenem-sensitive enzymes that stabilize peptidoglycans through 3 -> 3 cross-links. M. tuber-culosis encodes five L,D-transpeptidases (Ldt(Mt1)(-5)), of which Ldt(Mt3) is one of the less understood. Herein, we structurally characterized the apo and faropenem-acylated forms of Ldt(Mt)3 at 1.3 and 1.8 A resolution, respectively. These structures revealed a fold and catalytic diad similar to those of other Ldts(Mt) enzymes, supporting its involvement in transpeptidation reactions despite divergences in active site size and charges. The Ldt(Mt3)-faropenem structure indicated that faropenem is degraded after Cys-246 acylation, and possibly only beta-OH-butyrate or an acetyl group (C2H3O) covalently attached to the enzyme remains, an observation that strongly supports the notion that Ldt(Mt3) is inactivated by beta-lactams. Docking simulations with intact beta-lactams predicted key Ldt(Mt3) residues that interact with these antibiotics. We also characterized the heat of acylation involved in the binding and reaction of Ldt(Mt3) for ten beta-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 beta-lactams by Ldt(Mt3,) which may be useful for the development of additional beta-lactams with potential antitubercular activity. (AU)

FAPESP's process: 15/09188-8 - Biosynthesis of polyether and aminoglycoside antibiotics: structural investigation of unusual enzymes or with synthetic biology applicability
Grantee:Marcio Vinicius Bertacine Dias
Support type: Regular Research Grants
FAPESP's process: 10/15971-3 - Structural characterization of enzymes from antibiotic biosynthetic pathways with biotechnological interest
Grantee:Marcio Vinicius Bertacine Dias
Support type: Research Grants - Young Investigators Grants
FAPESP's process: 16/18721-4 - Structural basis of the elongation and cell division control in Mycobacterium tuberculosis and identification of new drug hits based in fragment trials
Grantee:Catharina dos Santos Silva
Support type: Scholarships in Brazil - Doctorate (Direct)