Deletion of PMP3 increases ketoconazole resistance by affecting plasma membrane potential in Candida albicans

IF 6.1 1区 生物学 Q1 MICROBIOLOGY Microbiological research Pub Date : 2024-09-27 DOI:10.1016/j.micres.2024.127918
Mengsen Zhu, Yanting Wang, Jiacheng Zhao, Zhishang Shi, Congcong Ma, Qilin Yu, Mingchun Li
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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.
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PMP3 的缺失会影响白色念珠菌的质膜电位,从而增加酮康唑的抗药性。
酮康唑是临床上常用的经典抗真菌药物。近年来,随着酮康唑使用量的增加,临床治疗中出现了越来越多的耐药菌株。众所周知,真菌通过多种途径获得耐药性,而酮康唑耐药性的分子机制仍有待全面探索。本研究发现,在几株临床分离的酮康唑耐药菌株中,小质膜蛋白编码基因PMP3的表达明显下调,表明PMP3的表达与酮康唑耐药之间存在一定的关系。通过敲除 PMP3,我们发现 Pmp3 的缺失会导致白色念珠菌对酮康唑的耐药性明显增加,这在小鼠全身感染模型中也得到了证实。我们进一步证实,在 pmp3Δ/Δ 突变体中,细胞膜流动性、质膜电位、通透性和麦角固醇分布等各种生理特性都发生了改变,这与细胞对酮康唑的耐药性增强有关。此外,过表达而非缺失 PMP3 会改变白僵菌的头状花序发育和生物膜形成能力。这项研究揭示了 Pmp3 对真菌病原体耐药性的改变所起的作用,可为新型抗真菌策略的开发提供指导。
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来源期刊
Microbiological research
Microbiological research 生物-微生物学
CiteScore
10.90
自引率
6.00%
发文量
249
审稿时长
29 days
期刊介绍: Microbiological Research is devoted to publishing reports on prokaryotic and eukaryotic microorganisms such as yeasts, fungi, bacteria, archaea, and protozoa. Research on interactions between pathogenic microorganisms and their environment or hosts are also covered.
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