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

Dong Liang Yang; Yan Ling HU; Zi Xin Yin; Gui Sheng Zeng; Dan LI; Yu Qian Zhang; Zhen Hua XU; Xiao Ming Guan; Li Xing Weng; Lian Hui Wang

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

Author: Dong Liang YANG ^{1
,

2} ; Yan Ling HU ³ ; Zi Xin YIN ³ ; Gui Sheng ZENG ⁴ ; Dan LI ³ ; Yu Qian ZHANG ³ ; Zhen Hua XU ⁵ ; Xiao Ming GUAN ⁶ ; Li Xing WENG ⁷ ; Lian Hui WANG ³
Author Information

1. Key Laboratory for Organic Electronics & Information Displays (KLOEID) and Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, Jiangsu, China
2. School of Physical and Mathematical Sciences, Nanjing Tech University (NanjingTech), Nanjing 211816, Jiangsu, China.
3. Key Laboratory for Organic Electronics & Information Displays (KLOEID) and Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, Jiangsu, China.
4. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Proteos 138673, Singapore.
5. Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
6. Department of Obstetrics & Gynecology, Baylor College of Medicine, 6651 Main Street, Suite F1050, Houston, Texas 77030, USA.
7. College of Geography and Biological Information, Nanjing University of Posts and Telecommunications, Nanjing 210023, Jiangsu, China.
Publication Type:Journal Article
Keywords: C. albicans; CDR1; Cis-2-dodecenoic acid; Combination; MDR1; azole-resistant
MeSH: Antifungal Agents; pharmacology; Burkholderia cenocepacia; chemistry; Candida albicans; drug effects; physiology; Candidiasis; drug therapy; Drug Resistance, Fungal; Fatty Acids, Monounsaturated; adverse effects; Fluconazole; pharmacology; Humans; Microbial Sensitivity Tests; Triazoles; metabolism
From: Biomedical and Environmental Sciences 2019;32(3):199-209
CountryChina
Language:English
Abstract: 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.