Sulfonamide-Based Inhibitors of Biotin Protein Ligase
as New Antibiotic Leads
Posted on 2019-08-21 - 14:44
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.
CITE THIS COLLECTION
DataCite
3 Biotech
3D Printing in Medicine
3D Research
3D-Printed Materials and Systems
4OR
AAPG Bulletin
AAPS Open
AAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)
Academic Medicine
Academic Pediatrics
Academic Psychiatry
Academic Questions
Academy of Management Discoveries
Academy of Management Journal
Academy of Management Learning and Education
Academy of Management Perspectives
Academy of Management Proceedings
Academy of Management Review
Lee, Kwang
Jun; Tieu, William; Blanco-Rodriguez, Beatriz; Paparella, Ashleigh S.; Yu, Jingxian; Hayes, Andrew; et al. (2019). Sulfonamide-Based Inhibitors of Biotin Protein Ligase
as New Antibiotic Leads. ACS Publications. Collection. https://doi.org/10.1021/acschembio.9b00463
or
Select your citation style and then place your mouse over the citation text to select it.
SHARE
Usage metrics
Read the peer-reviewed publication
AUTHORS (16)
KL
Kwang
Jun Lee
WT
William Tieu
BB
Beatriz Blanco-Rodriguez
AP
Ashleigh S. Paparella
JY
Jingxian Yu
AH
Andrew Hayes
JF
Jiage Feng
AM
Andrew C. Marshall
BN
Benjamin Noll
RM
Robert Milne
DC
Danielle Cini
MW
Matthew C. J. Wilce
GB
Grant W. Booker
JB
John B. Bruning
SP
Steven W. Polyak
AA
Andrew D. Abell
KEYWORDS
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