Exploration of the antibiotic potentiating activity of indolglyoxylpolyamines

Melissa M. Cadelis; Elliot I.W. Pike; Weirong  Kang; Zimei Wu; Marie Lise Bourguet-Kondracki; Marine Blanchet; Nicolas Vidal; Jean Michel Brunel; Brent R. Copp

doi:10.1016/j.ejmech.2019.111708

Exploration of the antibiotic potentiating activity of indolglyoxylpolyamines

Melissa M. Cadelis, Elliot I.W. Pike, Weirong Kang, Zimei Wu, Marie Lise Bourguet-Kondracki, Marine Blanchet, Nicolas Vidal, Jean Michel Brunel, Brent R. Copp^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

15 Citations (Scopus)

Abstract

A series of substituted di-indolglyoxylamido-spermine analogues were prepared and evaluated for intrinsic antimicrobial properties and the ability to enhance antibiotic action. As a compound class, intrinsic activity was typically observed towards Gram-positive bacteria and the fungus Cryptococcus neoformans, with notable exceptions being the 5-bromo- and 6-chloro-indole analogues which also exhibited modest activity (MIC 34–50 μM) towards the Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae. Several analogues enhanced the activity of doxycycline towards the Gram-negative bacteria Pseudomonas aeruginosa, E. coli, K. pneumoniae and Acinetobacter baumannii. Of particular note was the identification of five antibiotic enhancing analogues (5-Br, 7-F, 5-Me, 7-Me, 7-OMe) which also exhibited low to no cytotoxicity and red blood cell haemolytic properties. The mechanisms of action of the 5-Br and 7-F analogues were attributed to the ability to disrupt the integrity of, and depolarize, bacterial membranes.

Original language	English
Article number	111708
Journal	European Journal of Medicinal Chemistry
Volume	183
DOIs	https://doi.org/10.1016/j.ejmech.2019.111708
Publication status	Published - 1 Dec 2019
Externally published	Yes

User-Defined Keywords

Polyamine
Indole
Indolglyoxylamide
Potentiation
Antimicrobial

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2019.111708

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title = "Exploration of the antibiotic potentiating activity of indolglyoxylpolyamines",

abstract = "A series of substituted di-indolglyoxylamido-spermine analogues were prepared and evaluated for intrinsic antimicrobial properties and the ability to enhance antibiotic action. As a compound class, intrinsic activity was typically observed towards Gram-positive bacteria and the fungus Cryptococcus neoformans, with notable exceptions being the 5-bromo- and 6-chloro-indole analogues which also exhibited modest activity (MIC 34–50 μM) towards the Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae. Several analogues enhanced the activity of doxycycline towards the Gram-negative bacteria Pseudomonas aeruginosa, E. coli, K. pneumoniae and Acinetobacter baumannii. Of particular note was the identification of five antibiotic enhancing analogues (5-Br, 7-F, 5-Me, 7-Me, 7-OMe) which also exhibited low to no cytotoxicity and red blood cell haemolytic properties. The mechanisms of action of the 5-Br and 7-F analogues were attributed to the ability to disrupt the integrity of, and depolarize, bacterial membranes.",

keywords = "Polyamine, Indole, Indolglyoxylamide, Potentiation, Antimicrobial",

author = "Cadelis, {Melissa M.} and Pike, {Elliot I.W.} and Weirong Kang and Zimei Wu and Bourguet-Kondracki, {Marie Lise} and Marine Blanchet and Nicolas Vidal and Brunel, {Jean Michel} and Copp, {Brent R.}",

note = "Funding Information: We acknowledge funding from the Auckland Medical Research Foundation (1116001). We thank Dr. Michael Schmitz and Tony Chen for their assistance with the NMR and mass spectrometric data. Some of the antimicrobial screening was performed by CO-ADD (The Community for Antimicrobial Drug Discovery), funded by the Wellcome Trust (UK) and The University of Queensland (Australia). We thank Marcel Kaiser (Swiss Tropical Public Health Institute) for the L6 cytotoxicity data. Publisher Copyright: {\textcopyright} 2019 Elsevier Masson SAS. All rights reserved.",

year = "2019",

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doi = "10.1016/j.ejmech.2019.111708",

language = "English",

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AU - Cadelis, Melissa M.

AU - Pike, Elliot I.W.

AU - Kang, Weirong

AU - Wu, Zimei

AU - Bourguet-Kondracki, Marie Lise

AU - Blanchet, Marine

AU - Vidal, Nicolas

AU - Brunel, Jean Michel

AU - Copp, Brent R.

N1 - Funding Information: We acknowledge funding from the Auckland Medical Research Foundation (1116001). We thank Dr. Michael Schmitz and Tony Chen for their assistance with the NMR and mass spectrometric data. Some of the antimicrobial screening was performed by CO-ADD (The Community for Antimicrobial Drug Discovery), funded by the Wellcome Trust (UK) and The University of Queensland (Australia). We thank Marcel Kaiser (Swiss Tropical Public Health Institute) for the L6 cytotoxicity data. Publisher Copyright: © 2019 Elsevier Masson SAS. All rights reserved.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - A series of substituted di-indolglyoxylamido-spermine analogues were prepared and evaluated for intrinsic antimicrobial properties and the ability to enhance antibiotic action. As a compound class, intrinsic activity was typically observed towards Gram-positive bacteria and the fungus Cryptococcus neoformans, with notable exceptions being the 5-bromo- and 6-chloro-indole analogues which also exhibited modest activity (MIC 34–50 μM) towards the Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae. Several analogues enhanced the activity of doxycycline towards the Gram-negative bacteria Pseudomonas aeruginosa, E. coli, K. pneumoniae and Acinetobacter baumannii. Of particular note was the identification of five antibiotic enhancing analogues (5-Br, 7-F, 5-Me, 7-Me, 7-OMe) which also exhibited low to no cytotoxicity and red blood cell haemolytic properties. The mechanisms of action of the 5-Br and 7-F analogues were attributed to the ability to disrupt the integrity of, and depolarize, bacterial membranes.

AB - A series of substituted di-indolglyoxylamido-spermine analogues were prepared and evaluated for intrinsic antimicrobial properties and the ability to enhance antibiotic action. As a compound class, intrinsic activity was typically observed towards Gram-positive bacteria and the fungus Cryptococcus neoformans, with notable exceptions being the 5-bromo- and 6-chloro-indole analogues which also exhibited modest activity (MIC 34–50 μM) towards the Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae. Several analogues enhanced the activity of doxycycline towards the Gram-negative bacteria Pseudomonas aeruginosa, E. coli, K. pneumoniae and Acinetobacter baumannii. Of particular note was the identification of five antibiotic enhancing analogues (5-Br, 7-F, 5-Me, 7-Me, 7-OMe) which also exhibited low to no cytotoxicity and red blood cell haemolytic properties. The mechanisms of action of the 5-Br and 7-F analogues were attributed to the ability to disrupt the integrity of, and depolarize, bacterial membranes.

KW - Polyamine

KW - Indole

KW - Indolglyoxylamide

KW - Potentiation

KW - Antimicrobial

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DO - 10.1016/j.ejmech.2019.111708

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JF - European Journal of Medicinal Chemistry

M1 - 111708

ER -

Exploration of the antibiotic potentiating activity of indolglyoxylpolyamines

Abstract

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