1-(2-Hydroxybenzoyl)-thiosemicarbazides are promising antimicrobial agents targeting D-alanine-D-alanine ligase in bacterio

Alice Ameryckx, Léopold Thabault, Lionel Pochet, Serge Leimanis, Jacques Poupaert, Johan Wouters, Bernard Joris, Françoise Van Bambeke, Raphaël Frederick

Research output: Contribution to journalArticle

Abstract

The bacterial cell wall and the enzymes involved in peptidoglycan synthesis are privileged targets for the development of novel antibacterial agents. In this work, a series of 1-(2-hydroxybenzoyl)-thiosemicarbazides inhibitors of D-Ala-D-Ala ligase (Ddl) were designed and synthesized in order to target resistant strains of bacteria. Among these, the 4-(3,4-dichlorophenyl)-1-(2-hydroxybenzoyl)-3-thiosemicarbazide 29 was identified as a potent Ddl inhibitor with activity in the micromolar range. This compound, possessing strong antimicrobial activity including against multidrug resistant strains, was proven to act through a bactericidal mechanism and demonstrated very low cytotoxicity on THP-1 human monocytic cell line. Inhibition of Ddl activity by 29 was confirmed in bacterio using UPLC-MS/MS by demonstrating an increase in D-Ala intracellular pools accompanied by a commensurate decrease in D-Ala-D-Ala. Further structure-activity relationships (SARs) studies provided evidence that the hydroxyl substituent in the 2-position (R 1) of the benzoylthiosemicarbazide scaffold is essential for the enzymatic inhibition. This work thus highlights the 1-(2-hydroxybenzoyl)-thiosemicarbazide motif as a very promising tool for the development of novel antibacterial compounds acting through an interesting mechanism of action and low cytotoxicity.

LanguageEnglish
Pages324-338
Number of pages15
JournalEuropean journal of medicinal chemistry / Chimica therapeutica
Volume159
Issue number5
DOIs
Publication statusPublished - 5 Nov 2018

Fingerprint

Anti-Infective Agents
Cytotoxicity
Cells
Peptidoglycan
Structure-Activity Relationship
Scaffolds
Hydroxyl Radical
Cell Wall
Bacteria
Anti-Bacterial Agents
Cell Line
Enzymes
thiosemicarbazide
D-alanylalanine synthetase

Keywords

  • Antibiotics
  • Antimicrobial agents
  • Benzoylthiosemicarbazides
  • D-alanine-D-alanine ligase inhibitors
  • Structure-activity relationships

Cite this

Ameryckx, Alice ; Thabault, Léopold ; Pochet, Lionel ; Leimanis, Serge ; Poupaert, Jacques ; Wouters, Johan ; Joris, Bernard ; Van Bambeke, Françoise ; Frederick, Raphaël. / 1-(2-Hydroxybenzoyl)-thiosemicarbazides are promising antimicrobial agents targeting D-alanine-D-alanine ligase in bacterio. In: European journal of medicinal chemistry / Chimica therapeutica. 2018 ; Vol. 159, No. 5. pp. 324-338.
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1-(2-Hydroxybenzoyl)-thiosemicarbazides are promising antimicrobial agents targeting D-alanine-D-alanine ligase in bacterio. / Ameryckx, Alice; Thabault, Léopold; Pochet, Lionel; Leimanis, Serge; Poupaert, Jacques; Wouters, Johan; Joris, Bernard; Van Bambeke, Françoise; Frederick, Raphaël.

In: European journal of medicinal chemistry / Chimica therapeutica, Vol. 159, No. 5, 05.11.2018, p. 324-338.

Research output: Contribution to journalArticle

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AU - Ameryckx, Alice

AU - Thabault, Léopold

AU - Pochet, Lionel

AU - Leimanis, Serge

AU - Poupaert, Jacques

AU - Wouters, Johan

AU - Joris, Bernard

AU - Van Bambeke, Françoise

AU - Frederick, Raphaël

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