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Sulfonamide-Based Inhibitors of Biotin Protein Ligase as New Antibiotic Leads
journal contribution
posted on 2019-08-21, 14:44 authored by Kwang
Jun Lee, William Tieu, Beatriz Blanco-Rodriguez, Ashleigh S. Paparella, Jingxian Yu, Andrew Hayes, Jiage Feng, Andrew C. Marshall, Benjamin Noll, Robert Milne, Danielle Cini, Matthew C. J. Wilce, Grant W. Booker, John B. Bruning, Steven W. Polyak, Andrew D. AbellHere, 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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acyl phosphateStaphylococcus aureus BPLpharmacokinetic profileSa BPL Lys 187. Analoguesaureus ATCC 49775inhibitors 6interactionCompound 6K isulfonamide linker moietyenzyme assay resultsenergy estimationSulfonamide-Based InhibitorsX-ray crystallographyNew AntibioticBiotin Protein Ligaseβ- hydroxysulfonamidedeprotonated 6sulfonamide linkersdynamics simulationssulfonamide isostere
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