Synergistic mechanism for tetrandrine on fluconazole against Candida albicans through the mitochondrial aerobic respiratory metabolism pathway.
We found that tetrandrine (TET) can reverse the resistance of Candida albicans to fluconazole (FLC) and that this interaction is associated with the inhibition of drug efflux pumps. Mitochondrial aerobic respiration, which plays a major role in C. albicans metabolism, is the primary source of ATP for cellular processes, including the activation of efflux pumps. However, it was unclear if TET exerts its synergistic action against C. albicans via its impact on the mitochondrial aerobic respiratory metabolism. To investigate this mechanism, we examined the impact of FLC in the presence or absence of TET on two C. albicans strains obtained from a single parental source (FLC-sensitive strain CA-1 and FLC-resistant strain CA-16). We analysed key measures of energy generation and conversion, including the activity of respiration chain complexes I and III (CI and CIII), ATP synthase (CV) activity, and the generation of reactive oxygen species (ROS), and studied intracellular ATP levels and the mitochondrial membrane potential (ΔΨm), which has a critical impact on energy transport. Mitochondrial morphology was observed by confocal microscopy. Our functional analyses revealed that, compared with strains treated only with FLC, TET+FLC increased the ATP levels and decreased ΔΨm in CA-1, but decreased ATP levels and increased ΔΨm in CA-16 (P<0.05). Additionally, CI, CIII and CV activity decreased by 23-48%. The production of ROS increased by two- to threefold and mitochondrial morphology was altered in both strains. Our data suggested that TET impacted mitochondrial aerobic respiratory metabolism by influencing the generation and transport of ATP, reducing the utilization of ATP, and resulting in the inhibition of drug efflux pump activity. This activity contributed to the synergistic action of TET on FLC against C. albicans.
Guangdong Province Key Laboratory of Molecule Immunology and Antibody Engineering, Guangdong, PR China.|Clinical Medicine Postdoctoral Mobile Station, Jinan University, Guangdong, PR China.|First Affiliated Hospital and Institute of Mycology, Jinan University, Guangdong, PR China.
Hui
H
Guo
Scholl of Medicine, Jinan University, Guangdong, PR China.|Guangdong Province Key Laboratory of Molecule Immunology and Antibody Engineering, Guangdong, PR China.
Si Ming
SM
Xie
First Affiliated Hospital and Institute of Mycology, Jinan University, Guangdong, PR China.
Shui Xiu
SX
Li
First Affiliated Hospital and Institute of Mycology, Jinan University, Guangdong, PR China.
Yan Jun
YJ
Song
First Affiliated Hospital and Institute of Mycology, Jinan University, Guangdong, PR China.
Xia Lin
XL
Lv
First Affiliated Hospital and Institute of Mycology, Jinan University, Guangdong, PR China.
Hong
H
Zhang
D000255:Adenosine Triphosphate / Q000378:metabolism; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D044182:Benzylisoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects*; D025141:Drug Resistance, Fungal / Q000187:drug effects; D004357:Drug Synergism; D015725:Fluconazole / Q000493:pharmacokinetics / Q000494:pharmacology*; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism
D000935:Antifungal Agents; D044182:Benzylisoquinolines; D017382:Reactive Oxygen Species; C009438:tetrandrine; D000255:Adenosine Triphosphate; D015725:Fluconazole