Post-translational modifications confer amphotericin B resistance in Candida krusei isolated from a neutropenic patient

Frontiers in Immunology

Immunology

Mingwei Du¹  Xiaochun Xue²  Weiwei Yang³  Wenzhi Lei⁴  Jinzhou Xiao⁴  Li Zhang⁴ 

[1] Department of Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China;Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China;Department of Pharmacy, 905th Hospital of PLA Navy, Shanghai, China;Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China;Shanghai Engineering Research Center of Lung Transplantation, Shanghai, China;Institute of Dermatology, Naval Medical University, Shanghai, China;

关键词: Candida krusei;    neutropenia;    amphotericin B;    resistance;    succinylation;   

DOI  :  10.3389/fimmu.2023.1148681

 received in 2023-01-20, accepted in 2023-02-13,  发布年份 2023

来源: Frontiers

【 摘 要 】

Neutropenia is a common complication in the treatment of hematological diseases and the most common predisposing factor for invasion by fungi, such as Candida krusei. Recent studies have shown that C. krusei, a life-threatening pathogen, has developed resistance to amphotericin B (AMB). However, the mechanisms that led to the rapid emergence of this AMB-resistant phenotype are unclear. In this study, we found the sensitivity for AMB could be promoted by inhibiting histone acyltransferase activity and western blot analysis revealed differences in the succinylation levels of C. krusei isolated from immunocompromised patients and of the corresponding AMB-resistant mutant. By comparative succinyl-proteome analysis, we identified a total of 383 differentially expressed succinylated sites in with 344 sites in 134 proteins being upregulated in the AMB-resistant mutant, compared to 39 sites in 23 proteins in the wild-type strain. These differentially succinylated proteins were concentrated in the ribosome and cell wall. The critical pathways associated with these proteins included those involved in glycolysis, gluconeogenesis, the ribosome, and fructose and mannose metabolism. In particular, AMB resistance was found to be associated with enhanced ergosterol synthesis and aberrant amino acid and glucose metabolism. Analysis of whole-cell proteomes, confirmed by parallel reaction monitoring, showed that the key enzyme facilitating lysine acylation was significantly upregulated in the AMB-resistant strain. Our results suggest that lysine succinylation may play an indispensable role in the development of AMB resistance in C. krusei. Our study provides mechanistic insights into the development of drug resistance in fungi and can aid in efforts to stifle the emergence of AMB-resistant pathogenic fungi.

【 授权许可】

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Copyright © 2023 Zhang, Xiao, Du, Lei, Yang and Xue