Sulfonamide-based inhibitors of biotin protein ligase as new antibiotic leads
Date
2019
Authors
Lee, K.J.
Tieu, W.
Blanco-Rodriguez, B.
Paparella, A.S.
Yu, J.
Hayes, A.
Feng, J.
Marshall, A.C.
Noll, B.
Milne, R.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
ACS Chemical Biology, 2019; 14(9):1990-1997
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
Conference Name
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.
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Data source: Supporting information, https://doi.org/10.1021/acschembio.9b00463
Link to a related website: https://pubs.acs.org/doi/10.1021/acschembio.9b00463, Open Access via Unpaywall
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© 2019 American Chemical Society