A template guided approach to generating cell permeable inhibitors of Staphylococcus aureus biotin protein ligase

Ashleigh S. Paparella; Jiage Feng; Beatriz Blanco-Rodriguez; Zikai Feng; Wanida Phetsang; Mark A.T. Blaskovich; Matthew A. Cooper; Grant W. Booker; Steven W. Polyak; Andrew D. Abell

doi:10.1016/j.tet.2017.10.032

A template guided approach to generating cell permeable inhibitors of Staphylococcus aureus biotin protein ligase

Ashleigh S. Paparella, Jiage Feng, Beatriz Blanco-Rodriguez, Zikai Feng, Wanida Phetsang, Mark A.T. Blaskovich, Matthew A. Cooper, Grant W. Booker, Steven W. Polyak, Andrew D. Abell

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Inhibitors of biotin protein ligase (BPL) are novel antimicrobial compounds with the potential to treat infections caused by bacteria resistant to current antibiotics. A novel BPL inhibitor (12, K_i 1.4 μM) was synthesized from biotin acetylene and an azide-functionalized analogue of fluorescent nitrobenzofurazan by Cu(I) catalysed cycloaddition and also by template guided synthesis using wild-type BPL from Staphylococcus aureus. LC/HRMS-based detection provides improved sensitivity over previous reports using a mutant BPL, with demonstrated applicability to other BPLs. Super-imaging fluorescence microscopy demonstrated the accumulation of 12 in the cytoplasm of S. aureus, but not Escherichia coli. This novel fluorescent probe can be used to gain new insights into the mechanism of uptake, efflux and metabolism of BPL inhibitors in S. aureus.

Original language	English (US)
Pages (from-to)	1175-1183
Number of pages	9
Journal	Tetrahedron
Volume	74
Issue number	12
DOIs	https://doi.org/10.1016/j.tet.2017.10.032
State	Published - Mar 22 2018
Externally published	Yes

Keywords

Antibiotic
Azide-alkyne cycloaddition
Biotin protein ligase
Enzyme inhibitors
Staphylococcus aureus

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1016/j.tet.2017.10.032

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@article{d4b83c83d5634f24921bc64939af5fcc,

title = "A template guided approach to generating cell permeable inhibitors of Staphylococcus aureus biotin protein ligase",

abstract = "Inhibitors of biotin protein ligase (BPL) are novel antimicrobial compounds with the potential to treat infections caused by bacteria resistant to current antibiotics. A novel BPL inhibitor (12, Ki 1.4 μM) was synthesized from biotin acetylene and an azide-functionalized analogue of fluorescent nitrobenzofurazan by Cu(I) catalysed cycloaddition and also by template guided synthesis using wild-type BPL from Staphylococcus aureus. LC/HRMS-based detection provides improved sensitivity over previous reports using a mutant BPL, with demonstrated applicability to other BPLs. Super-imaging fluorescence microscopy demonstrated the accumulation of 12 in the cytoplasm of S. aureus, but not Escherichia coli. This novel fluorescent probe can be used to gain new insights into the mechanism of uptake, efflux and metabolism of BPL inhibitors in S. aureus.",

keywords = "Antibiotic, Azide-alkyne cycloaddition, Biotin protein ligase, Enzyme inhibitors, Staphylococcus aureus",

author = "Paparella, {Ashleigh S.} and Jiage Feng and Beatriz Blanco-Rodriguez and Zikai Feng and Wanida Phetsang and Blaskovich, {Mark A.T.} and Cooper, {Matthew A.} and Booker, {Grant W.} and Polyak, {Steven W.} and Abell, {Andrew D.}",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",

year = "2018",

month = mar,

day = "22",

doi = "10.1016/j.tet.2017.10.032",

language = "English (US)",

volume = "74",

pages = "1175--1183",

journal = "Tetrahedron",

issn = "0040-4020",

publisher = "Elsevier Limited",

number = "12",

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TY - JOUR

T1 - A template guided approach to generating cell permeable inhibitors of Staphylococcus aureus biotin protein ligase

AU - Paparella, Ashleigh S.

AU - Feng, Jiage

AU - Blanco-Rodriguez, Beatriz

AU - Feng, Zikai

AU - Phetsang, Wanida

AU - Blaskovich, Mark A.T.

AU - Cooper, Matthew A.

AU - Booker, Grant W.

AU - Polyak, Steven W.

AU - Abell, Andrew D.

PY - 2018/3/22

Y1 - 2018/3/22

N2 - Inhibitors of biotin protein ligase (BPL) are novel antimicrobial compounds with the potential to treat infections caused by bacteria resistant to current antibiotics. A novel BPL inhibitor (12, Ki 1.4 μM) was synthesized from biotin acetylene and an azide-functionalized analogue of fluorescent nitrobenzofurazan by Cu(I) catalysed cycloaddition and also by template guided synthesis using wild-type BPL from Staphylococcus aureus. LC/HRMS-based detection provides improved sensitivity over previous reports using a mutant BPL, with demonstrated applicability to other BPLs. Super-imaging fluorescence microscopy demonstrated the accumulation of 12 in the cytoplasm of S. aureus, but not Escherichia coli. This novel fluorescent probe can be used to gain new insights into the mechanism of uptake, efflux and metabolism of BPL inhibitors in S. aureus.

AB - Inhibitors of biotin protein ligase (BPL) are novel antimicrobial compounds with the potential to treat infections caused by bacteria resistant to current antibiotics. A novel BPL inhibitor (12, Ki 1.4 μM) was synthesized from biotin acetylene and an azide-functionalized analogue of fluorescent nitrobenzofurazan by Cu(I) catalysed cycloaddition and also by template guided synthesis using wild-type BPL from Staphylococcus aureus. LC/HRMS-based detection provides improved sensitivity over previous reports using a mutant BPL, with demonstrated applicability to other BPLs. Super-imaging fluorescence microscopy demonstrated the accumulation of 12 in the cytoplasm of S. aureus, but not Escherichia coli. This novel fluorescent probe can be used to gain new insights into the mechanism of uptake, efflux and metabolism of BPL inhibitors in S. aureus.

KW - Antibiotic

KW - Azide-alkyne cycloaddition

KW - Biotin protein ligase

KW - Enzyme inhibitors

KW - Staphylococcus aureus

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U2 - 10.1016/j.tet.2017.10.032

DO - 10.1016/j.tet.2017.10.032

M3 - Article

AN - SCOPUS:85032744102

SN - 0040-4020

VL - 74

SP - 1175

EP - 1183

JO - Tetrahedron

JF - Tetrahedron

IS - 12

ER -

A template guided approach to generating cell permeable inhibitors of Staphylococcus aureus biotin protein ligase

Abstract

Keywords

ASJC Scopus subject areas

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