Repurposing bioactive aporphine alkaloids as efflux pump inhibitors

Autor: Fatma Gizem Avci, Jean-Michel Jault, Cédric Orelle, Maxime Guillerminet, Çağlayan Gürer, Gizem Gulsoy Toplan, Eldin Kurpejovic, Basak Atas, Berna Sariyar Akbulut, Cemile Selin Aksoy
Přispěvatelé: Avci, Fatma Gizem, Atas, Basak, Aksoy, Cemile Selin, Kurpejovic, Eldin, Toplan, Gizem Gulsoy, Gurer, Caglayan, Guillerminet, Maxime, Orelle, Cedric, Jault, Jean-Michel, Akbulut, Berna Sariyar, Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry (MMSB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Turkey
Berberine
[SDV]Life Sciences [q-bio]
ANTIBACTERIAL ACTIVITY
Bacillus subtilis
medicine.disease_cause
MULTIDRUG-RESISTANT PHENOTYPE
01 natural sciences
chemistry.chemical_compound
Drug Discovery
Alkaloid
BINDING
Efflux pump inhibition
ComputingMilieux_MISCELLANEOUS
media_common
Molecular Structure
biology
Chemistry
Drug Synergism
General Medicine
Anti-Bacterial Agents
3. Good health
BmrA
Biochemistry
ESCHERICHIA-COLI
Efflux
medicine.drug
Drug
EXPRESSION
Aporphines
media_common.quotation_subject
Microbial Sensitivity Tests
BACILLUS-SUBTILIS
Alkaloids
Bacterial Proteins
Escherichia coli
medicine
Doxorubicin
Papaver
Bmr
Roemerine
STAPHYLOCOCCUS-AUREUS
Pharmacology
IDENTIFICATION
010405 organic chemistry
TRANSPORTER
Drug Repositioning
Membrane Transport Proteins
Substrate (chemistry)
Biological Transport
Plant Components
Aerial
biology.organism_classification
0104 chemical sciences
010404 medicinal & biomolecular chemistry
Zdroj: Fitoterapia
Fitoterapia, Elsevier, 2019, 139, pp.104371. ⟨10.1016/j.fitote.2019.104371⟩
ISSN: 0367-326X
1873-6971
DOI: 10.1016/j.fitote.2019.104371⟩
Popis: Extrusion of drugs or drug-like compounds through bacterial efflux pumps is a serious health issue that leads to loss in drug efficacy. Combinatorial therapies of low-efficacy drugs with efflux pump inhibitors may help to restore the activities of such drugs. In this quest, natural products are attractive molecules, since in addition to their wide range of bioactivities they may inhibit efflux pumps. The current work repurposed the bioactive alkaloid roemerine as a potential efflux pump inhibitor. In Bacillus subtilis, both Bmr and BmrA, belonging to the major facilitator and the ATP-binding cassette superfamilies, respectively, were found to be inhibited by roemerine. Scanning electron microscopy and RNA-Seq analyses showed that it potentiated the effect of berberine. Growth rates and checkerboard assays confirmed the synergy of roemerine and berberine and that roemerine prevented berberine efflux by inhibiting Bmr. Transport assays with inverted membrane vesicles prepared from Escherichia coli overexpressing BmrA showed that increasing roemerine concentration decreased the transport of doxorubicin, the BmrA substrate, confirming that roemerine may also be considered as an inhibitor of BmrA. Thus, these findings suggest that conjugation of roemerine to substrates of efflux pumps, Bmr and BmrA, may help to potentiate the activity of their drug substrates.
Databáze: OpenAIRE
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