Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/121835
Citations
Scopus Web of Science® Altmetric
?
?
Type: Journal article
Title: Sulfonamide-based inhibitors of biotin protein ligase as new antibiotic leads
Author: Lee, K.J.
Tieu, W.
Blanco-Rodriguez, B.
Paparella, A.S.
Yu, J.
Hayes, A.
Feng, J.
Marshall, A.C.
Noll, B.
Milne, R.
Cini, D.
Wilce, M.C.J.
Booker, G.W.
Bruning, J.B.
Polyak, S.W.
Abell, A.D.
Citation: ACS Chemical Biology, 2019; 14(9):1990-1997
Publisher: ACS Publications
Issue Date: 2019
ISSN: 1554-8929
1554-8937
Statement of
Responsibility: 
Kwang Jun LeeWilliam TieuBeatriz Blanco-RodriguezAshleigh S. PaparellaJingxian YuAndrew HayesJiage FengAndrew C. MarshallBenjamin NollRobert MilneDanielle CiniMatthew C. J. WilceGrant W. BookerJohn B. BruningSteven W. PolyakAndrew D. Abell
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.
Keywords: Animals; Mice; Rats; Staphylococcus aureus; Sulfonamides; Carbon-Nitrogen Ligases; Bacterial Proteins; Enzyme Inhibitors; Anti-Bacterial Agents; Crystallography, X-Ray; Microbial Sensitivity Tests; Drug Stability; Drug Design; Molecular Dynamics Simulation
Rights: © 2019 American Chemical Society
RMID: 0030133434
DOI: 10.1021/acschembio.9b00463
Grant ID: http://purl.org/au-research/grants/nhmrc/1068885
http://purl.org/au-research/grants/arc/CE140100 003
http://purl.org/au-research/grants/nhmrc/GN1147538
Appears in Collections:Physics publications

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.