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https://hdl.handle.net/2440/121835
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dc.contributor.author | Lee, K.J. | - |
dc.contributor.author | Tieu, W. | - |
dc.contributor.author | Blanco-Rodriguez, B. | - |
dc.contributor.author | Paparella, A.S. | - |
dc.contributor.author | Yu, J. | - |
dc.contributor.author | Hayes, A. | - |
dc.contributor.author | Feng, J. | - |
dc.contributor.author | Marshall, A.C. | - |
dc.contributor.author | Noll, B. | - |
dc.contributor.author | Milne, R. | - |
dc.contributor.author | Cini, D. | - |
dc.contributor.author | Wilce, M.C.J. | - |
dc.contributor.author | Booker, G.W. | - |
dc.contributor.author | Bruning, J.B. | - |
dc.contributor.author | Polyak, S.W. | - |
dc.contributor.author | Abell, A.D. | - |
dc.date.issued | 2019 | - |
dc.identifier.citation | ACS Chemical Biology, 2019; 14(9):1990-1997 | - |
dc.identifier.issn | 1554-8929 | - |
dc.identifier.issn | 1554-8937 | - |
dc.identifier.uri | http://hdl.handle.net/2440/121835 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | 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 | - |
dc.language.iso | en | - |
dc.publisher | ACS Publications | - |
dc.rights | © 2019 American Chemical Society | - |
dc.source.uri | http://dx.doi.org/10.1021/acschembio.9b00463 | - |
dc.subject | Animals | - |
dc.subject | Mice | - |
dc.subject | Rats | - |
dc.subject | Staphylococcus aureus | - |
dc.subject | Sulfonamides | - |
dc.subject | Carbon-Nitrogen Ligases | - |
dc.subject | Bacterial Proteins | - |
dc.subject | Enzyme Inhibitors | - |
dc.subject | Anti-Bacterial Agents | - |
dc.subject | Crystallography, X-Ray | - |
dc.subject | Microbial Sensitivity Tests | - |
dc.subject | Drug Stability | - |
dc.subject | Drug Design | - |
dc.subject | Molecular Dynamics Simulation | - |
dc.title | Sulfonamide-based inhibitors of biotin protein ligase as new antibiotic leads | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1021/acschembio.9b00463 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1068885 | - |
dc.relation.grant | http://purl.org/au-research/grants/arc/CE140100 003 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/GN1147538 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Lee, K.J. [0000-0003-3006-5094] | - |
dc.identifier.orcid | Tieu, W. [0000-0002-7161-4152] | - |
dc.identifier.orcid | Yu, J. [0000-0002-6489-5988] | - |
dc.identifier.orcid | Hayes, A. [0000-0001-8038-1656] | - |
dc.identifier.orcid | Marshall, A.C. [0000-0002-9770-4594] | - |
dc.identifier.orcid | Booker, G.W. [0000-0001-7207-4699] | - |
dc.identifier.orcid | Bruning, J.B. [0000-0002-6919-1824] | - |
dc.identifier.orcid | Polyak, S.W. [0000-0002-8458-5194] | - |
dc.identifier.orcid | Abell, A.D. [0000-0002-0604-2629] | - |
Appears in Collections: | Aurora harvest 4 Physics publications |
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