Design, synthesis and evaluation of D-alanyl-D-alanine ligase inhibitors : an attractive target for the development of antimicrobial agents
(2020)
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- Abstract
- As the phenomenon of antibiotic resistance is dramatically increasing these days, the search for new therapeutic targets less vulnerable to resistance appears as a real need. The cell wall of bacteria and the enzymes involved in its synthesis are prime targets for many clinically important antibiotics, which inhibit the late stages of peptidoglycan biosynthetic pathway. However, the resistance phenomena have revealed the need to target other steps of peptidoglycan synthesis. D-alanyl-D-alanine ligase (Ddl) is of particular interest as it utilizes a substrate, D-alanine, which is specific for peptidoglycan biosynthesis and essential for bacterial growth. Our work focused on the development of Ddl inhibitors in order to target resistant strains of bacteria. The synthesis of benzoylthiosemicarbazides and their pharmacomodulations allowed identifying potent Ddl inhibitors with activities in the low micromolar range and good antimicrobial potencies, including against multidrug resistant strains. The in bacterio target was then determined by UPLC-MS dosage of intracellular peptidoglycan precursors levels in response to the three most promising derivatives of our study. An increase in D-Ala pools accompanied by a decrease in D-Ala-D-Ala were observed, thus confirming that these compounds exert, at least in part, their antibacterial activity through Ddl inhibition. This work thus highlights very promising tools for the development of novel antibacterial agents acting through an original mechanism of action.
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Ameryckx, A. (2020). Design, synthesis and evaluation of D-alanyl-D-alanine ligase inhibitors : an attractive target for the development of antimicrobial agents. https://hdl.handle.net/2078.5/96555