1: Curr Med Chem. 2009;16(20):2566-80.

DD-Ligases as a Potential Target for Antibiotics: Past, Present and Future.

Tytgat I, Colacino E, Tulkens PM, Poupaert JH, Prévost M, Van Bambeke F.

Pharmacologie cellulaire et moléculaire, UCL7370 avenue Mounier 73, 1200
Brussels, Belgium. francoise.vanbambeke@uclouvain.be.

DD-ligases catalyze the synthesis of the D-Ala-D-Ala and D-Ala-D-Ser dipeptides
or the D Ala-D-Lac depsipeptide in an early step of peptidoglycan synthesis.
Their function is essential for bacterial growth and specific to bacteria, making
them attractive targets for the development of novel antibiotics. This review
examines the biochemical and structural features of these enzymes and presents
the main families of inhibitors described so far. Over the last 20 years, 7
structures of DD-ligases have been solved by X-ray crystallography, giving a
detailed view of the general topology of the active site and of the residues in
the catalytic pocket that play a central role in substrate recognition. This has 
paved the way to the rational design of inhibitors, which can be classified as
(i) analogues of substrates, (ii) analogues of the product of the reaction, (iii)
analogues of the transition state, and (iv) original scaffolds discovered by
screening or by rational computer-aided design. The three first strategies have
led to molecules that are polar by nature and have therefore poor access to their
cytosolic target. The fourth one is potentially most promising as it yields more 
diverse structures. The most active molecules show affinity constants in the
microM range, but microbiological evaluation remains scarce (typical MIC 1-8 mg/L
for the tested compounds). These data strongly suggest targeting DD-ligases is a 
promising approach for discovery of new antibiotics. Future research should,
however, aim at finding more potent inhibitors endowed with the appropriate
pharmacokinetic properties that ensure access to their intracellular target.

PMID: 19601798 [PubMed - in process]

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