Sulfonamide-Based Inhibitors of Biotin Protein Ligase as New Antibiotic Leads
العنوان: | Sulfonamide-Based Inhibitors of Biotin Protein Ligase as New Antibiotic Leads |
---|---|
المؤلفون: | Kwangjun Lee, Andrew D. Abell, Steven W. Polyak, Beatriz Blanco-Rodriguez, John B. Bruning, Danielle Cini, Grant W. Booker, Robert W. Milne, Benjamin Noll, Andrew J. Hayes, Andrew C Marshall, Ashleigh S. Paparella, Jiage Feng, Matthew C.J. Wilce, Jingxian Yu, William Tieu |
المساهمون: | Lee, Kwang Jun, Tieu, William, Blanco-Rodriguez, Beatriz, Paparella, Ashleigh S, Yu, Jingxian, Hayes, Andrew, Feng, Jiage, Marshall, Andrew C, Noll, Benjamin, Milne, Robert, Cini, Danielle, Wilce, Matthew CJ, Booker, Grant W, Bruning, John B, Polyak, Steven W, Abell, Andrew D |
المصدر: | ACS Chemical Biology. 14:1990-1997 |
بيانات النشر: | American Chemical Society (ACS), 2019. |
سنة النشر: | 2019 |
مصطلحات موضوعية: | pharmacokinetic profile, 0301 basic medicine, Staphylococcus aureus, medicine.drug_class, Antibiotics, Microbial Sensitivity Tests, Molecular Dynamics Simulation, Crystallography, X-Ray, medicine.disease_cause, 01 natural sciences, Biochemistry, metabolic stability, Microbiology, Mice, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Drug Stability, Biotin, medicine, Animals, Carbon-Nitrogen Ligases, Enzyme Inhibitors, chemistry.chemical_classification, Sulfonamides, DNA ligase, 010405 organic chemistry, molecular dynamics simulations, General Medicine, Phosphate, Anti-Bacterial Agents, Rats, 0104 chemical sciences, Sulfonamide, 030104 developmental biology, chemistry, Drug Design, Molecular Medicine |
الوصف: | 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. Refereed/Peer-reviewed |
تدمد: | 1554-8937 1554-8929 |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::17972eb42541dd574d7fb900e1b5a4a3 https://doi.org/10.1021/acschembio.9b00463 |
حقوق: | CLOSED |
رقم الأكسشن: | edsair.doi.dedup.....17972eb42541dd574d7fb900e1b5a4a3 |
قاعدة البيانات: | OpenAIRE |
تدمد: | 15548937 15548929 |
---|