Cis-2-dodecenoic Acid Mediates Its Synergistic Effect with Triazoles by Interfering with Efflux Pumps in Fluconazole-resistant Candida albicans.

Authors:
Yan Ling Hu
Yan Ling Hu
Shanghai Tenth People's Hospital
Gui Sheng Zeng
Gui Sheng Zeng
Institute of Molecular and Cell Biology
Singapore | Singapore
Yu Qian Zhang
Yu Qian Zhang
Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors

Biomed Environ Sci 2019 Mar;32(3):199-209

Key Laboratory for Organic Electronics & Information Displays (KLOEID) and Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, Jiangsu, China.

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 (qRT-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 qRT-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 mRNA 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.

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Source
http://www.besjournal.com/Articles/Archive/2019/No3/201904/t
Publisher Site
http://dx.doi.org/10.3967/bes2019.027DOI Listing
March 2019
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