Objective To evaluate the synergy of the Burkholderia signaling molecule cis-2-dodecenoic acid(BDSF) and fluconazole(FLU) or itraconazole(ITRA) against two azole-resistant C. albicans clinical isolates in vitro and in...Objective To evaluate the synergy of the Burkholderia signaling molecule cis-2-dodecenoic acid(BDSF) and fluconazole(FLU) or itraconazole(ITRA) against two azole-resistant C. albicans clinical isolates in vitro and in vivo. Methods Minimum inhibitory concentrations(MICs) of antibiotics against two azole-resistant C. albicans were measured by the checkerboard technique, E-test, and time-kill assay. In vivo antifungal synergy testing was performed on mice. Analysis of the relative gene expression levels of the strains was conducted by quantitative reverse-transcription polymerase chain reaction(qR T-PCR). Results BDSF showed highly synergistic effects in combination with FLU or ITRA with a fractional inhibitory concentration index of ≤ 0.08. BDSF was not cytotoxic to normal human foreskin fibroblast cells at concentrations of up to 300 μg/mL. The qR T-PCR results showed that the combination of BDSF and FLU/ITRA significantly inhibits the expression of the efflux pump genes CDR1 and MDR1 via suppression of the transcription factors TAC1 and MRR1, respectively, when compared with FLU or ITRA alone. No dramatic difference in the mR NA expression levels of ERG1, ERG11, and UPC2 was found, which indicates that the drug combinations do not significantly interfere with UPC2-mediated ergosterol levels. In vivo experiments revealed that combination therapy can be an effective therapeutic approach to treat candidiasis. Conclusion The synergistic effects of BDSF and azoles may be useful as an alternative approach to control azole-resistant Candida infections.展开更多
基金financially supported by the National Natural Science Foundation of China [81273409]the Program for Changjiang Scholars and Innovative Research Team in University [IRT_15R37]the Ministry of Science and Technology of China [2017YFA0205301]
文摘Objective To evaluate the synergy of the Burkholderia signaling molecule cis-2-dodecenoic acid(BDSF) and fluconazole(FLU) or itraconazole(ITRA) against two azole-resistant C. albicans clinical isolates in vitro and in vivo. Methods Minimum inhibitory concentrations(MICs) of antibiotics against two azole-resistant C. albicans were measured by the checkerboard technique, E-test, and time-kill assay. In vivo antifungal synergy testing was performed on mice. Analysis of the relative gene expression levels of the strains was conducted by quantitative reverse-transcription polymerase chain reaction(qR T-PCR). Results BDSF showed highly synergistic effects in combination with FLU or ITRA with a fractional inhibitory concentration index of ≤ 0.08. BDSF was not cytotoxic to normal human foreskin fibroblast cells at concentrations of up to 300 μg/mL. The qR T-PCR results showed that the combination of BDSF and FLU/ITRA significantly inhibits the expression of the efflux pump genes CDR1 and MDR1 via suppression of the transcription factors TAC1 and MRR1, respectively, when compared with FLU or ITRA alone. No dramatic difference in the mR NA expression levels of ERG1, ERG11, and UPC2 was found, which indicates that the drug combinations do not significantly interfere with UPC2-mediated ergosterol levels. In vivo experiments revealed that combination therapy can be an effective therapeutic approach to treat candidiasis. Conclusion The synergistic effects of BDSF and azoles may be useful as an alternative approach to control azole-resistant Candida infections.
