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Novel Naphthalene-N-sulfonyl-d-glutamic Acid Derivatives as Inhibitors of MurD, a Key Peptidoglycan Biosynthesis Enzyme,

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posted on 2008-12-11, 00:00 authored by Jan Humljan, Miha Kotnik, Carlos Contreras-Martel, Didier Blanot, Uroš Urleb, Andréa Dessen, Tom Šolmajer, Stanislav Gobec
Mur ligases have essential roles in the biosynthesis of peptidoglycan, and they represent attractive targets for the design of novel antibacterials. MurD (UDP-N-acetylmuramoyl-l-alanine:d-glutamate ligase) is the second enzyme in the series of Mur ligases, and it catalyzes the addition of d-glutamic acid (d-Glu) to the cytoplasmic intermediate UDP-N-acetylmuramoyl-l-alanine (UMA). Because of the high binding affinity of d-Glu toward MurD, we synthesized and biochemically evaluated a series of N-substituted d-Glu derivatives as potential inhibitors of MurD from E. coli, which allowed us to explore the structure−activity relationships. The substituted naphthalene-N-sulfonyl-d-Glu inhibitors, which were synthesized as potential transition-state analogues, displayed IC50 values ranging from 80 to 600 μM. In addition, the high-resolution crystal structures of MurD in complex with four novel inhibitors revealed details of the binding mode of the inhibitors within the active site of MurD. Structure−activity relationships and cocrystal structures constitute an excellent starting point for further development of novel MurD inhibitors of this structural class.

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