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Published on: December 28, 2017
Deletion of PMP3 increases ketoconazole resistance by affecting plasma membrane potential in Candida albicans
Mengsen Zhu1, Yanting Wang1, Jiacheng Zhao1
1Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Science, Nankai University, Tianjin 300071, China.
Abstract:
Ketoconazole is a classical antifungal drug commonly used in the clinic. With the increased use of ketoconazole in recent years, an increasing number of drug-resistant strains have emerged during clinical treatment. It is well known that fungi acquire drug resistance in multiple ways, while the molecular mechanisms underlying ketoconazole resistance remain for comprehensive exploration. In this study, we found that the expression of the small plasma membrane protein-encoding gene PMP3 was significantly down-regulated in several clinically isolated ketoconazole-resistant strains, indicating the relationship between PMP3 expression and ketoconazole resistance. By knocking out the PMP3, we found that the absence of the Pmp3 resulted in a significant increase in resistance of Candida albicans to ketoconazole, which was also confirmed in a systemic infection model in mice. We further demonstrated that various physiological properties, such as cell membrane fluidity, plasma membrane potential, permeability and ergosterol distribution were altered in the pmp3Δ/Δ mutant, which is associated with the enhanced cellular resistance to ketoconazole. In addition, overexpression rather than deletion of PMP3 alters the hyphal development and biofilm formation capacity in C. albicans. This study reveals the contribution of Pmp3 to alteration of drug resistance in fungal pathogens, which may guide the development of novel antifungal strategies.
Insights
The PMP3 gene
Area of Science:
- Mycology
- Molecular Biology
- Drug Resistance
Background:
- Ketoconazole is a widely used antifungal agent.
- Emerging ketoconazole-resistant fungal strains pose a clinical challenge.
- Molecular mechanisms of fungal drug resistance require further elucidation.
Purpose of the Study:
- To investigate the role of the PMP3 gene in ketoconazole resistance in Candida albicans.
- To explore the molecular mechanisms underlying PMP3-mediated drug resistance.
- To assess the impact of PMP3 on fungal physiology and virulence.
Main Methods:
- Gene expression analysis of PMP3 in resistant strains.
- Generation and characterization of PMP3 knockout (pmp3Δ/Δ) and overexpression mutants.
- Assessment of antifungal susceptibility, cell membrane properties, and hyphal development.
- Evaluation of a systemic infection model in mice.
Main Results:
- PMP3 expression was significantly downregulated in clinical ketoconazole-resistant isolates.
- Deletion of PMP3 (pmp3Δ/Δ) markedly increased Candida albicans resistance to ketoconazole.
- pmp3Δ/Δ mutants exhibited altered cell membrane fluidity, potential, permeability, and ergosterol distribution.
- PMP3 overexpression affected hyphal development and biofilm formation.
Conclusions:
- Pmp3 plays a crucial role in modulating ketoconazole resistance in Candida albicans.
- Altered membrane properties in pmp3Δ/Δ mutants contribute to enhanced drug resistance.
- Pmp3 is a potential target for developing novel antifungal strategies against resistant fungal pathogens.
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