Format

Send to

Choose Destination
ACS Chem Biol. 2019 Aug 21. doi: 10.1021/acschembio.9b00463. [Epub ahead of print]

Sulfonamide-Based Inhibitors of Biotin Protein Ligase as New Antibiotic Leads.

Author information

1
Department of Chemistry, School of Physical Sciences , University of Adelaide , Adelaide , South Australia 5005 , Australia.
2
Centre for Nanoscale BioPhotonics (CNBP) , University of Adelaide , Adelaide , South Australia 5005 , Australia.
3
Department of Molecular and Cellular Biology, School of Biological Sciences , University of Adelaide , Adelaide , South Australia 5005 , Australia.
4
School of Pharmacy & Medical Sciences , University of South Australia , Adelaide , South Australia 5000 , Australia.
5
Department of Biochemistry, School of Biomedical Science , Monash University , Clayton , Victoria 3800 , Australia.
6
Institute of Photonics and Advanced Sensing (IPAS), School of Biological Sciences , University of Adelaide , Adelaide , South Australia 5005 , Australia.

Abstract

Here, we report the design, synthesis, and evaluation of a series of inhibitors of Staphylococcus aureus BPL (SaBPL), where the central acyl phosphate of the natural intermediate biotinyl-5'-AMP (1) is replaced by a sulfonamide isostere. Acylsulfamide (6) and amino sulfonylurea (7) showed potent in vitro inhibitory activity (Ki = 0.007 ± 0.003 and 0.065 ± 0.03 μM, respectively) and antibacterial activity against S. aureus ATCC49775 with minimum inhibitory concentrations of 0.25 and 4 μg/mL, respectively. Additionally, the bimolecular interactions between the BPL and inhibitors 6 and 7 were defined by X-ray crystallography and molecular dynamics simulations. The high acidity of the sulfonamide linkers of 6 and 7 likely contributes to the enhanced in vitro inhibitory activities by promoting interaction with SaBPL Lys187. Analogues with alkylsulfamide (8), β-ketosulfonamide (9), and β-hydroxysulfonamide (10) isosteres were devoid of significant activity. Binding free energy estimation using computational methods suggests deprotonated 6 and 7 to be the best binders, which is consistent with enzyme assay results. Compound 6 was unstable in whole blood, leading to poor pharmacokinetics. Importantly, 7 has a vastly improved pharmacokinetic profile compared to that of 6 presumably due to the enhanced metabolic stability of the sulfonamide linker moiety.

PMID:
31407891
DOI:
10.1021/acschembio.9b00463

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center