Luteolin potentiates the effects of aminoglycoside and β-lactam antibiotics against methicillin-resistant Staphylococcus aureus in vitro
Dae-Ki JoungOk‐Hwa KangYun‐Soo SeoTian ZhouYoung-Seob LeeSin‐Hee HanSu‐Hyun MunRyong KongHojun SongDong‐Won ShinDong-Yeul Kwon
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Abstract:
Methicillin-resistant Staphylococcus aureus (MRSA) infection has become a serious clinical problem worldwide, and alternative natural or combination drug therapies are required for its treatment. The aim of the present study was to examined the antimicrobial activity of luteolin (LUT) against MRSA. Luteolin is a polyphenolic flavonoid compound with a wide spectrum of biological activities. The antimicrobial activities of LUT and the antibiotics ampicillin (AM), oxacillin (OX) and gentamicin (GT), used alone or in combination, were evaluated against five clinical MRSA isolates and two reference strains using a minimum inhibitory concentration (MIC) assay, MTT colorimetric assay, checkerboard dilution test and time-kill assay. The MIC of LUT against all strains was found to be 62.5 µg/ml. The combinations of LUT and antibiotics exhibited a synergistic effect against MRSA in the majority of cases, as determined by the checkerboard method. Time-kill curves revealed that a combination of LUT with AM, OX or GT significantly reduced bacterial counts, which dropped below the lowest detectable limit after 24 h. These results indicate that LUT potentiates the effects of β-lactam and aminoglycoside antibiotics against MRSA.Keywords:
Checkerboard
The effect of ampicillin 25 mg/ml, gentamicin 5 mg/l and methotrexate 10 & 70 mg/l, alone and in combination, was tested for their influence on human polymorphonuclear cell-locomotion, using zymosan or a bacterial filtrate of E. coli, with or without 0.25 and 0.025 mg/l of ampicillin and gentamicin, respectively, as attractants. Methotrexate and gentamicin alone decreased the locomotion, using zymosan as attractant. No effect was observed using the pure bacterial filtrate. The filtrate containing antibiotics displayed a lower ability to induce locomotion when the leucocytes had been pre-treated with antibiotics alone or in combination with methotrexate but not with methotrexate alone. Aspects of these findings are discussed.
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Listeria monocytogenes infections are most common in newborn infants and persons with impaired defense mechanisms. There are reports of successful treatment with ampicillin alone: however, there is uncertainty as to what regimen constitutes the most effective therapy. The purpose of this study was to illustrate the in-vitro synergism between ampicillin and gentamicin against L. monocytogenes. Seven strains of L. monocytogenes isolated from bloods or cerebrospinal fluids of infants and three control strains obtained from the Center for Disease Control were tested. Minimal inhibitory concentrations of ampicillin and gentamicin were determined in Todd-Hewitt broth with an inoculum of 10(5) organisms/ml. Killing curves were determined for ampicillin 6 microgram/ml, gentamicin, 0.5 microgram/ml, and the combination of ampicillin, 6 microgram/ml, plus gentamicin, 0.5 microgram/ml. Incubation of approximately 10(7) organisms/ml with these concentrations of ampicillin and gentamicin caused no significant reduction in the viable bacterial population in 24 hours. The combination, on the other hand, was bactericidal in all seven strains isolated from patients and one control strain. The authors believe the ultimate test of the superiority of this combination to ampicillin alone must come from clinical studies. However, the synergistic and bactericidal effects of ampicillin with gentamicin may be very desirable in treatment of newborns and patients with underlying disease.
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Combinations of aminoglycosides plus ampicillin usually are necessary for the satisfactory management of serious Enterococcus faecalis sepsis. A study in a South London hospital demonstrated that 7% of all E. faecalis, and 30% of those from blood cultures, were highly gentamicin resistant. Addition of gentamicin confers no benefit to the treatment of these organisms with ampicillin. We looked at the susceptibility pattern of these organisms in vitro and concluded that ampicillin plus ciprofloxacin offered the best available combination.
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A simple combined agar-strip test (CAST), involving filter paper strips charged with 20 micrograms of ampicillin or 40 micrograms of gentamicin, accurately detected high-level gentamicin resistance among 43 of 146 isolates of Enterococcus faecalis and additive activity of ampicillin plus gentamicin against 101 of 103 (98%) isolates of E. faecalis with moderate-level gentamicin resistance (MLGR). All 15 MLGR Enterococcus faecium isolates were moderately to highly resistant to ampicillin; 5 isolates with moderate resistance to ampicillin (minimal inhibitory concentrations = 16 micrograms/ml) were additively inhibited by ampicillin plus gentamicin, whereas the highly ampicillin-resistant E. faecium isolates yielded an indifferent effect with the CAST procedure.
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Luteolin is a naturally occurring flavone that reportedly has anti-inflammatory effects. Because most luteolin is conjugated following intestinal absorption, free luteolin is likely present at low levels in the body. Therefore, luteolin metabolites are presumably responsible for luteolin bioactivity. Here we confirmed that luteolin glucuronides, especially luteolin-3'-O-glucuronide, are the major metabolites found in plasma after oral administration of luteolin (aglycone) or luteolin glucoside (luteolin-7-O-glucoside) to rats. Luteolin-4'-O-glucuronide and luteolin-7-O-glucuronide were also detectable together with luteolin-3'-O-glucuronide in the liver, kidney, and small intestine. Next, we prepared these luteolin glucuronides and compared the anti-inflammatory effects of luteolin and luteolin glucuronides on gene expression in lipopolysaccharide-treated RAW264.7 cells. Luteolin glucuronides, especially luteolin-7-O-glucuronide, reduced expression of inflammatory genes in the cells, although their effects were weaker than those of luteolin. These results indicate that the active compound responsible for the anti-inflammatory effect of luteolin in vivo would be luteolin glucuronide and/or residual luteolin.
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