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Structure and function of the Mur enzymes: development of novel inhibitors
Ahmed El Zoeiby1, François Sanschagrin, Roger C Levesque
1Centre de Recherche sur la Fonction, Structure et Ingénierie des Protéines, Faculté de Médecine, Pavillon Charles-Eugène Marchand, Université Laval, Ste-Foy, Québec, Canada, G1K 7P4.
Abstract:
One of the biggest challenges for recent medical research is the continuous development of new antibiotics interacting with bacterial essential mechanisms. The machinery for peptidoglycan biosynthesis is a rich source of crucial targets for antibacterial chemotherapy. The cytoplasmic steps of the biosynthesis of peptidoglycan precursor, catalysed by a series of Mur enzymes, are excellent candidates for drug development. There has been growing interest in these bacterial enzymes over the last decade. Many studies attempted to understand the detailed mechanisms and structural features of the key enzymes MurA to MurF. Only MurA is inhibited by a known antibiotic, fosfomycin. Several attempts made to develop novel inhibitors of this pathway are discussed in this review. Three novel inhibitors of MurA were identified recently. 4-Thiazolidinone compounds were designed as MurB inhibitors. Many phosphinic acid derivatives and substrate analogues were identified as inhibitors of the MurC to MurF amino acid ligases.
Insights
Developing new antibiotics targeting bacterial peptidoglycan biosynthesis is crucial. This review discusses novel inhibitors for Mur enzymes (MurA-MurF), key targets in antibacterial drug development.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Drug Discovery
Background:
- Antibiotic resistance necessitates novel antibacterial agents.
- Peptidoglycan biosynthesis is an essential bacterial pathway and a promising target for new drugs.
- The Mur enzymes (MurA-MurF) catalyze cytoplasmic steps in peptidoglycan precursor synthesis.
Purpose of the Study:
- To review recent advancements in the development of novel inhibitors targeting the Mur enzymes.
- To highlight key enzymes and strategies for antibacterial drug discovery within the peptidoglycan biosynthesis pathway.
Main Methods:
- Literature review of studies on Mur enzyme inhibitors.
- Analysis of recently identified inhibitors for MurA, MurB, and MurC-MurF enzymes.
- Discussion of structural features and mechanisms of inhibition.
Main Results:
- Fosfomycin is the only known antibiotic targeting MurA.
- Three novel inhibitors of MurA have been recently identified.
- 4-Thiazolidinone compounds show potential as MurB inhibitors.
- Phosphinic acid derivatives and substrate analogues are effective inhibitors of MurC-MurF ligases.
Conclusions:
- The Mur enzyme pathway remains a fertile ground for developing new antibacterial agents.
- Targeting Mur enzymes offers a promising strategy to combat bacterial infections and overcome resistance.
- Continued research into novel inhibitors is essential for advancing antibiotic chemotherapy.