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|Title:||Sulfonamide-based inhibitors of biotin protein ligase as new antibiotic leads|
|Citation:||ACS Chemical Biology, 2019; 14(9):1990-1997|
|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.|
Microbial Sensitivity Tests
Molecular Dynamics Simulation
|Rights:||© 2019 American Chemical Society|
|Appears in Collections:||Aurora harvest 4|
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