Spermine Derivatives of Indole-3-carboxylic Acid,Indole-3-acetic Acid and Indole-3-acrylic Acid as Gram-Negative Antibiotic Adjuvants |
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Authors: | Dr. Melissa M. Cadelis Steven A. Li Dr. Marie-Lise Bourguet-Kondracki Dr. Marine Blanchet Hana Douafer Dr. Jean Michel Brunel Prof. Brent R. Copp |
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Affiliation: | 1. School of Chemical Sciences, The University of Auckland, Private Bag, 92019 Auckland 1142, New Zealand;2. Laboratoire Molécules de Communication et Adaptation des Micro-organismes UMR 7245 CNRS Muséum National d'Histoire Naturelle, 57 rue Cuvier (C.P. 54), 75005 Paris, France;3. Aix-Marseille Université, INSERM, SSA, MCT, 13385 Marseille, France |
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Abstract: | The discovery of new antibiotic adjuvants is an attractive option for overcoming antimicrobial resistance. We have previously reported the discovery of a bis-6-bromoindolglyoxylamide derivative of spermine as being able to enhance the action of antibiotics against Gram-negative bacteria but suffers from being cytotoxic and red-blood cell haemolytic. A series of analogues was prepared exploring variation of the indolglyoxylamide unit, to include indole-3-acrylic, indole-3-acetic and indole-3-carboxylate units, and evaluated for antibiotic enhancing properties against a range of Gram-negative bacteria, and for intrinsic antimicrobial, cytotoxic and haemolytic properties. Two spermine derivatives, bearing 5-bromo-indole-3-acetic acid ( 17 ) and 5-methoxy-indole-3-acrylic acid ( 14 ) end groups were found to exhibit good to moderate antibiotic adjuvant activities for doxycycline towards the Gram-negative bacteria Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae, but with more modest intrinsic antimicrobial activity and greatly reduced cytotoxic and haemolytic properties. The mechanism of action of the latter derivative identified its ability to disrupt the outer membranes of bacteria and to inhibit the AcrAB-TolC efflux pump directly or by inhibiting the proton gradient. |
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Keywords: | Indoles polyamines adjuvants enhancers antibiotics |
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