Structure-guided design and synthesis of ATP-competitive N-acyl-substituted sulfamide d-alanine-d-alanine ligase inhibitors.

Antibiotics Enzyme Inhibitors Staphylococcus aureus d-alanine-d-alanine ligase

Journal

Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298

Informations de publication

Date de publication:
15 Dec 2023
Historique:
received: 29 08 2023
revised: 10 10 2023
accepted: 24 10 2023
pubmed: 11 11 2023
medline: 11 11 2023
entrez: 10 11 2023
Statut: ppublish

Résumé

d-Alanine-d-alanine ligase (Ddl) catalyses the ATP-dependent formation of d-Ala-d-Ala, a critical component in bacterial cell wall biosynthesis and is a validated target for new antimicrobial agents. Here, we describe the structure-guided design, synthesis, and evaluation of ATP-competitive N-acyl-substituted sulfamides 27-36, 42, 46, 47 as inhibitors of Staphylococcus aureus Ddl (SaDdl). A crystal structure of SaDdl complexed with ATP and d-Ala-d-Ala (PDB: 7U9K) identified ATP-mimetic 8 as an initial scaffold for further inhibitor design. Evaluation of 8 in SaDdl enzyme inhibition assays revealed the ability to reduce enzyme activity to 72 ± 8 % (IC

Identifiants

DOI: 10.1016/j.bmc.2023.117509 PMID: 37948922
pubmed: 37948922
pii: S0968-0896(23)00357-7
doi: 10.1016/j.bmc.2023.117509
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

117509

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Auteurs

Rouven Becker (R)

Department of Chemistry, School of Physics, Chemistry and Earth Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia; Institute for Photonics and Advanced Sensing, (IPAS), School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia; Centre for Nanoscale BioPhotonics (CNBP), University of Adelaide, Adelaide, South Australia 5005, Australia.

Jordan L Pederick (JL)

Institute for Photonics and Advanced Sensing, (IPAS), School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia.

Edward G Dawes (EG)

Department of Chemistry, School of Physics, Chemistry and Earth Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia; Centre for Nanoscale BioPhotonics (CNBP), University of Adelaide, Adelaide, South Australia 5005, Australia.

John B Bruning (JB)

Institute for Photonics and Advanced Sensing, (IPAS), School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia.

Andrew D Abell (AD)

Department of Chemistry, School of Physics, Chemistry and Earth Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia; Institute for Photonics and Advanced Sensing, (IPAS), School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia; Centre for Nanoscale BioPhotonics (CNBP), University of Adelaide, Adelaide, South Australia 5005, Australia. Electronic address: andrew.abell@adelaide.edu.au.

Classifications MeSH