N-Thio-β-lactams targeting L,D-transpeptidase-2, with activity against drug-resistant strains of Mycobacterium tuberculosis
Martelli, Giulia ; Pessatti, Tomas Bohn ; Steiner, Eva Maria LU
; Cirillo, Martina
; Caso, Carolina
; Bisognin, Francesco
; Landreh, Michael
; Monte, Paola Dal
; Giacomini, Daria
and Schnell, Robert
(2021)
In Cell Chemical Biology
28(9).
p.5-1332
- Abstract
Effective treatment of tuberculosis is frequently hindered by the emerging antimicrobial resistance of Mycobacterium tuberculosis. The present study evaluates monocyclic β-lactam compounds targeting the mycobacterial cell wall remodeling. Novel N-thio-β-lactams were designed, synthesized, and characterized on the L,D-transpeptidase-2, a validated target in M. tuberculosis. The candidates were evaluated in biochemical assays identifying five compounds presenting target-specific kinetic constants equal or superior to meropenem, a carbapenem currently considered for tuberculosis therapy. Mass spectrometry in line with the crystal structures of five target-ligand complexes revealed that the N-thio-β-lactams act via an unconventional mode of... (More)
Effective treatment of tuberculosis is frequently hindered by the emerging antimicrobial resistance of Mycobacterium tuberculosis. The present study evaluates monocyclic β-lactam compounds targeting the mycobacterial cell wall remodeling. Novel N-thio-β-lactams were designed, synthesized, and characterized on the L,D-transpeptidase-2, a validated target in M. tuberculosis. The candidates were evaluated in biochemical assays identifying five compounds presenting target-specific kinetic constants equal or superior to meropenem, a carbapenem currently considered for tuberculosis therapy. Mass spectrometry in line with the crystal structures of five target-ligand complexes revealed that the N-thio-β-lactams act via an unconventional mode of adduct formation, transferring the thio-residues from the lactam ring to the active-site cysteine of LdtMt2. The resulting stable adducts lead to a long-term inactivation of the target protein. Finally, the candidates were evaluated in vitro against a drug-susceptible and multidrug-resistant clinical isolates of M. tuberculosis, confirming the antimycobacterial effect of these novel compounds.
(Less)
- author
- Martelli, Giulia
; Pessatti, Tomas Bohn
; Steiner, Eva Maria
LU
; Cirillo, Martina
; Caso, Carolina
; Bisognin, Francesco
; Landreh, Michael
; Monte, Paola Dal
; Giacomini, Daria
and Schnell, Robert
- publishing date
- 2021-09-16
- type
- Contribution to journal
- publication status
- published
- keywords
- adduct structure, antibiotic resistance, covalent inhibitor, L,D-transpeptidase, Ldt, Mycobacterium tuberculosis, β-lactam
- in
- Cell Chemical Biology
- volume
- 28
- issue
- 9
- pages
- 5 - 1332
- publisher
- Elsevier
- external identifiers
-
- pmid:33826941
- scopus:85104947258
- ISSN
- 2451-9456
- DOI
- 10.1016/j.chembiol.2021.03.008
- language
- English
- LU publication?
- no
- additional info
- Publisher Copyright: © 2021 The Authors
- id
- dcecc7c9-f6d0-4802-b638-d706a04091a0
- date added to LUP
- 2024-06-24 11:29:01
- date last changed
- 2024-07-08 11:03:15
@article{dcecc7c9-f6d0-4802-b638-d706a04091a0,
abstract = {{<p>Effective treatment of tuberculosis is frequently hindered by the emerging antimicrobial resistance of Mycobacterium tuberculosis. The present study evaluates monocyclic β-lactam compounds targeting the mycobacterial cell wall remodeling. Novel N-thio-β-lactams were designed, synthesized, and characterized on the L,D-transpeptidase-2, a validated target in M. tuberculosis. The candidates were evaluated in biochemical assays identifying five compounds presenting target-specific kinetic constants equal or superior to meropenem, a carbapenem currently considered for tuberculosis therapy. Mass spectrometry in line with the crystal structures of five target-ligand complexes revealed that the N-thio-β-lactams act via an unconventional mode of adduct formation, transferring the thio-residues from the lactam ring to the active-site cysteine of Ldt<sub>Mt2</sub>. The resulting stable adducts lead to a long-term inactivation of the target protein. Finally, the candidates were evaluated in vitro against a drug-susceptible and multidrug-resistant clinical isolates of M. tuberculosis, confirming the antimycobacterial effect of these novel compounds.</p>}},
author = {{Martelli, Giulia and Pessatti, Tomas Bohn and Steiner, Eva Maria and Cirillo, Martina and Caso, Carolina and Bisognin, Francesco and Landreh, Michael and Monte, Paola Dal and Giacomini, Daria and Schnell, Robert}},
issn = {{2451-9456}},
keywords = {{adduct structure; antibiotic resistance; covalent inhibitor; L,D-transpeptidase; Ldt; Mycobacterium tuberculosis; β-lactam}},
language = {{eng}},
month = {{09}},
number = {{9}},
pages = {{5--1332}},
publisher = {{Elsevier}},
series = {{Cell Chemical Biology}},
title = {{N-Thio-β-lactams targeting L,D-transpeptidase-2, with activity against drug-resistant strains of Mycobacterium tuberculosis}},
url = {{http://dx.doi.org/10.1016/j.chembiol.2021.03.008}},
doi = {{10.1016/j.chembiol.2021.03.008}},
volume = {{28}},
year = {{2021}},
}