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

• Published in: Journal of medicinal chemistry Vol. 51; no. 23; pp. 7486 - 7494
• Main Authors: Humljan, Jan, Kotnik, Miha, Contreras-Martel, Carlos, Blanot, Didier, Urleb, Uroš, Dessen, Andréa, Šolmajer, Tom, Gobec, Stanislav
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.12.2008; Amer Chemical Soc
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Binding Sites - drug effects; Biological and medical sciences; Chemistry, Medicinal; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glutamic Acid - analogs & derivatives; Glutamic Acid - chemistry; Glutamic Acid - pharmacology; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Structure; Naphthalenes - chemistry; Peptide Synthases - antagonists & inhibitors; Peptidoglycan - biosynthesis; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Stereoisomerism; Structure-Activity Relationship; ADDING ENZYME; DESIGN; L-ALANINE; PHOSPHINATE INHIBITORS; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; DRUG DISCOVERY; POTENTIAL INHIBITORS; CELL-WALL BIOSYNTHESIS; LIGASE; Sulfonamide; Carbon-nitrogen ligases; Enzyme; Enzyme inhibitor; Biosynthesis; Binding site; Naphthalene derivatives; In vitro; Peptidoglycan; α-Aminoacid; Structure activity relation; Ligases; Carboxamide; UDP-N-acetylmuramoylalanine-D-glutamate ligase; Antibacterial agent; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800762u

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.