Sulfonamide-based inhibitors of biotin protein ligase as new antibiotic leads.

Here we report the design, synthesis, and evaluation of a series of inhibitors of S. aureus BPL (SaBPL), where the central acylphosphate 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 also antibacterial activity against S. aureus ATCC49775 with a minimum inhibitory concentration (MIC) of 0.25 and 4 µg/ml respectively. Additionally, the bimolecular interactions between the BPL and the inhibitors 6 and 7 were defined by X-ray crystallography and molecular dynamics (MD) 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 suggest 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 6 presumably due to the enhanced metabolic stability of the sulfonamide linker moiety.