Spermine Derivatives of Indole‐3‐carboxylic Acid, Indole‐3‐acetic Acid and Indole‐3‐acrylic Acid as Gram‐Negative Antibiotic Adjuvants

Autor: Brent R. Copp, Marie-Lise Bourguet-Kondracki, Jean Michel Brunel, Marine Blanchet, Steven A. Li, Melissa M. Cadelis, Hana Douafer
Přispěvatelé: School of Chemical Sciences [Auckland], University of Auckland [Auckland], Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), Brunel, Jean Michel, Muséum national d'Histoire naturelle (MNHN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Indoles
medicine.drug_class
Carboxylic acid
polyamines
Antibiotics
Spermine
Microbial Sensitivity Tests
01 natural sciences
Biochemistry
antibiotics
Structure-Activity Relationship
chemistry.chemical_compound
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Drug Discovery
Escherichia coli
medicine
General Pharmacology
Toxicology and Pharmaceutics
ComputingMilieux_MISCELLANEOUS
Pharmacology
Indole test
chemistry.chemical_classification
Dose-Response Relationship
Drug
Indoleacetic Acids
Molecular Structure
biology
[CHIM.ORGA]Chemical Sciences/Organic chemistry
010405 organic chemistry
Chemistry
Organic Chemistry
biology.organism_classification
Antimicrobial
Anti-Bacterial Agents
0104 chemical sciences
3. Good health
Klebsiella pneumoniae
010404 medicinal & biomolecular chemistry
adjuvants
Pseudomonas aeruginosa
[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Molecular Medicine
enhancers
Efflux
Indole-3-acetic acid
Bacteria
Zdroj: ChemMedChem
ChemMedChem, 2020, ⟨10.1002/cmdc.202000359⟩
ChemMedChem, Wiley-VCH Verlag, 2021, 16 (3), pp.513-523. ⟨10.1002/cmdc.202000359⟩
ChemMedChem, Wiley-VCH Verlag, 2020, ⟨10.1002/cmdc.202000359⟩
ISSN: 1860-7179
1860-7187
DOI: 10.1002/cmdc.202000359⟩
Popis: International audience; 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.
Databáze: OpenAIRE
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