Combinatorial Activity of Flavonoids with Antibiotics Against Drug-Resistant Staphylococcus aureus.
The use of resistance-modifying agents is a potential strategy that is used to prolong the effective life of antibiotics in the face of increasing antibiotic resistance. Since certain flavonoids are potent bacterial efflux pump inhibitors, we assessed morin, rutin, quercetin, hesperidin, and (+)-catechin for their combined activity with the antibiotics ciprofloxacin, tetracycline, erythromycin, oxacillin, and ampicillin against drug-resistant strains of Staphylococcus aureus, including methicillin-resistant S. aureus. Four established methods were used to determine the combined efficacy of each combination: microdilution checkerboard assays, time-kill determinations, the Etest, and dual disc-diffusion methods. The cytotoxicity of the flavonoids was additionally evaluated in a mouse fibroblast cell line. Quercetin and its isomer morin decreased by 3- to 16-fold the minimal inhibitory concentration of ciprofloxacin, tetracycline, and erythromycin against some S. aureus strains. Rutin, hesperidin, and (+)-catechin did not promote any potentiation of antibiotics. Despite the potential cytotoxicity of these phytochemicals at a high concentration (fibroblast IC50 of 41.8 and 67.5 mg/L, respectively), quercetin is commonly used as a supplement for several therapeutic purposes. All the methods, with exception of the time-kill assay, presented a high degree of congruence without any apparent strain specificity.
1 LEPABE, Department of Chemical Engineering, Faculty of Engineering, University of Porto , Porto, Portugal .
Ana Cristina
AC
Abreu
2 Life and Health Sciences Research Institute (ICVS), University of Minho , Braga, Portugal .|3 ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães , Portugal .
Sofia C
SC
Serra
1 LEPABE, Department of Chemical Engineering, Faculty of Engineering, University of Porto , Porto, Portugal .|4 CECAV, Veterinary and Animal Science Research Center, Veterinary Science Department, University of Trás-os-Montes and Alto Douro , Vila Real, Portugal .
Anabela
A
Borges
4 CECAV, Veterinary and Animal Science Research Center, Veterinary Science Department, University of Trás-os-Montes and Alto Douro , Vila Real, Portugal .
Maria José
MJ
Saavedra
5 Manchester Pharmacy School, The University of Manchester , Manchester, United Kingdom .
Andrew J
AJ
Mcbain
2 Life and Health Sciences Research Institute (ICVS), University of Minho , Braga, Portugal .|3 ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães , Portugal .
António J
AJ
Salgado
1 LEPABE, Department of Chemical Engineering, Faculty of Engineering, University of Porto , Porto, Portugal .
Manuel
M
Simões
D000667:Ampicillin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002392:Catechin / Q000494:pharmacology; D002939:Ciprofloxacin / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000502:physiology; D004359:Drug Therapy, Combination; D004917:Erythromycin / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D006569:Hesperidin / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D010068:Oxacillin / Q000494:pharmacology; D011794:Quercetin / Q000494:pharmacology; D012431:Rutin / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D013752:Tetracycline / Q000494:pharmacology; D047309:Flavones
D000667:Ampicillin; D000900:Anti-Bacterial Agents; D002392:Catechin; D002939:Ciprofloxacin; D004917:Erythromycin; D005419:Flavonoids; D006569:Hesperidin; D010068:Oxacillin; D011794:Quercetin; D012431:Rutin; D013752:Tetracycline; C008548:morin; D047309:Flavones