title: C-Geranylated flavonoids from Paulownia tomentosa fruits with antimicrobial potential and synergistic activity with antibiotics.
abstract: Context C-6-Geranylated flavonoids possess promising biological activities. These substances could be a source of lead compounds for the development of therapeutics. Objective The study was designed to evaluate their antibacterial and antileishmanial activity. Materials and methods C-6-Geranylated flavanones were tested in micromolar concentrations against promastigote forms of Leishmania brazilensis, L. donovani, L. infantum, and L. panamensis against methicillin-resistant Staphylococcus aureus (MRSA); and synergistic potential with antibiotics was analyzed. IC50 values (after 72 h) were calculated and compared with that of miltefosine. Flow cytometry and DNA fragmentation analysis were used the mechanism of the effect. Geranylated flavanones or epigallocatechin gallate were combined with oxacillin, tetracycline, and ciprofloxacin, and the effects of these two-component combinations were evaluated. Minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) were established (after 24 h), the synergy was measured by the checkerboard titration technique, and the sums of the fractional inhibitory concentrations (∑FICs) were computed. Results 3'-O-Methyl-5'-O-methyldiplacone and 3'-O-methyldiplacone showed good antileishmanial activities (IC50 8-42 μM). 3'-O-Methyl-5'-hydroxydiplacone activates the apoptotic death at leishmanias, the effect of 3'-O-methyl-5'-O-methyldiplacone has another mechanism. The test of the antibacterial activity showed good effects of 3'-O-methyldiplacol and mimulone against MRSA (MIC 2-16 μg/mL), and in six cases, the results showed synergistic effects when combined with oxacillin. Synergistic effects were also found for the combination of epigallocatechin gallate with tetracycline or oxacillin. Conclusion This work demonstrates anti-MRSA and antileishmanial potential of geranylated flavanones and uncovers their promising synergistic activities with antibiotics. In addition, the mechanism of antileishmanial effect is proposed.
authors.affiliation: a Department of Natural Drugs , Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno , Brno , Czech Republic ;
authors.forename: Alice
authors.initials: A
authors.lastname: Navrátilová
authors.affiliation: b Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , Prague , Czech Republic ;
authors.forename: Ondřej
authors.initials: O
authors.lastname: Nešuta
authors.affiliation: a Department of Natural Drugs , Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno , Brno , Czech Republic ;
authors.forename: Irena
authors.initials: I
authors.lastname: Vančatová
authors.affiliation: c Department of Infectious Diseases and Microbiology , University of Veterinary and Pharmaceutical Sciences Brno , Brno , Czech Republic ;|d CEITEC VFU, University of Veterinary and Pharmaceutical Sciences Brno , Brno , Czech Republic ;
authors.forename: Alois
authors.initials: A
authors.lastname: Čížek
authors.affiliation: e Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca , Salamanca , Spain ;
authors.forename: Ruben E
authors.initials: RE
authors.lastname: Varela-M
authors.affiliation: f Laboratorio de Immunología y Parasitología Molecular , CIETUS, Facultad de Farmacia, Universidad de Salamanca , Salamanca ; Spain .
authors.forename: Julio
authors.initials: J
authors.lastname: López-Abán
authors.affiliation: e Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca , Salamanca , Spain ;
authors.forename: Janny A
authors.initials: JA
authors.lastname: Villa-Pulgarin
authors.affiliation: e Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca , Salamanca , Spain ;
authors.forename: Faustino
authors.initials: F
authors.lastname: Mollinedo
authors.affiliation: f Laboratorio de Immunología y Parasitología Molecular , CIETUS, Facultad de Farmacia, Universidad de Salamanca , Salamanca ; Spain .
authors.forename: Antonio
authors.initials: A
authors.lastname: Muro
authors.affiliation: g National Reference Laboratory for Antibiotics , National Institute of Public Health , Prague , Czech Republic ;
authors.forename: Helena
authors.initials: H
authors.lastname: Žemličková
authors.affiliation: a Department of Natural Drugs , Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno , Brno , Czech Republic ;
authors.forename: Daniela
authors.initials: D
authors.lastname: Kadlecová
authors.affiliation: a Department of Natural Drugs , Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno , Brno , Czech Republic ;|h Department of Molecular Biology and Pharmaceutical Biotechnology , Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno , Brno , Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Šmejkal
mesh_terms: D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology*; D000977:Antiparasitic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology*; D005638:Fruit; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development; D019684:Magnoliopsida / Q000737:chemistry; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D008517:Phytotherapy; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D010946:Plants, Medicinal; D054876:Prenylation; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D000977:Antiparasitic Agents; D005419:Flavonoids; D010936:Plant Extracts
keywords: Flavonoid; Leishmania; MRSA; geranyl; synergy