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https://hdl.handle.net/2440/121835
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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 |
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 |
Published version: | http://dx.doi.org/10.1021/acschembio.9b00463 |
Appears in Collections: | Aurora harvest 4 Physics publications |
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