白念珠菌对棘白菌素类药物耐药机制的研究进展

doi:10.35541/cjd.20210273

中华皮肤科杂志 ›› 2022, Vol. 55 ›› Issue (12): 1114-1117.doi: 10.35541/cjd.20210273

白念珠菌对棘白菌素类药物耐药机制的研究进展

杨璐段志敏李岷

中国医学科学院、北京协和医学院皮肤病研究所江苏省皮肤病与性病分子生物学重点实验室，南京 210042

收稿日期:2021-04-02 修回日期:2021-11-04 发布日期:2022-12-05
通讯作者: 李岷 E-mail:limin@pumcderm.cams.cn
基金资助:
国家自然科学基金（81773338）；中国医学科学院医学与健康科技创新工程项目（2017-I2M-1-017）；南京市国家级临床医学中心培育计划项目（2019060001）

Mechanisms underlying the resistance of Candida albicans to echinocandin antifungals

Yang Lu, Duan Zhimin, Li Min

Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China

Received:2021-04-02 Revised:2021-11-04 Published:2022-12-05
Contact: Li Min E-mail:limin@pumcderm.cams.cn
Supported by:
National Natural Science Foundation of China（81773338）; CAMS Innovation Fund for Medical Sciences（2017-I2M-1-017）; The Nanjing Incubation Program for National Clinical Research Center （2019060001）

摘要/Abstract

摘要： 【摘要】随着棘白菌素类抗真菌药物的应用，对其耐药的白念珠菌菌株越来越多。已发现白念珠菌对棘白菌素类药物耐药主要与FKS突变、MSH2突变、ERG3突变及生物膜形成、细胞自身应激反应、几丁质含量增高、膜鞘脂合成等相关。本文综述白念珠菌相关耐药基因及可能的耐药调控机制，有助于临床克服和预防棘白菌素耐药，探索治疗白念珠菌感染的新靶点，开发新药物。

关键词: 白色念珠菌, 抗药性, 真菌, 棘白菌素类, 点突变, FKS

Abstract: 【Abstract】 With the application of echinocandin antifungals, more and more resistant Candida albicans strains have been detected. It has been reported that mechanisms underlying the resistance of Candida albicans to echinocandin antifungals mainly involve FKS, MSH2 and ERG3 gene mutations, biofilm formation, cellular stress response, compensatory increases in chitin, sphingolipid synthesis, etc. This review focuses on echinocandin resistance-related genes and underlying mechanisms in Candida albicans, which will help to overcome and prevent echinocandin resistance in clinical practice, and explore new therapeutic targets and drugs for Candida albicans infection.

Key words: Candida albicans, Antifungal drug resistance, Echinocandin, Point mutations, FKS

杨璐段志敏李岷. 白念珠菌对棘白菌素类药物耐药机制的研究进展[J]. 中华皮肤科杂志, 2022,55(12):1114-1117. doi:10.35541/cjd.20210273

Yang Lu, Duan Zhimin, Li Min. Mechanisms underlying the resistance of Candida albicans to echinocandin antifungals[J]. Chinese Journal of Dermatology, 2022, 55(12): 1114-1117.doi:10.35541/cjd.20210273

参考文献 34

［1］	Lee Y, Puumala E, Robbins N, et al. Antifungal drug resistance: molecular mechanisms in Candida albicans and beyond［J］. Chem Rev, 2021,121（6）:3390⁃3411. doi: 10.1021/acs.chemrev. 0c00199.
［2］	Mesini A, Mikulska M, Giacobbe DR, et al. Changing epidemiology of candidaemia: increase in fluconazole⁃resistant Candida parapsilosis［J］. Mycoses, 2020,63（4）:361⁃368. doi: 10.1111/myc.13050.
［3］	Coste AT, Kritikos A, Li J, et al. Emerging echinocandin⁃resistant Candida albicans and glabrata in Switzerland［J］. Infection, 2020,48（5）: 761⁃766. doi: 10.1007/s15010⁃020⁃01475⁃8.
［4］	Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America［J］. Clin Infect Dis, 2016,62（4）:e1⁃50. doi: 10.1093/cid/civ933.
［5］	Pappas PG. Invasive candidiasis［J］. Infect Dis Clin North Am, 2006,20（3）:485⁃506. doi: 10.1016/j.idc.2006.07.004.
［6］	Shields RK, Nguyen MH, Press EG, et al. Abdominal candidiasis is a hidden reservoir of echinocandin resistance［J］. Antimicrob Agents Chemother, 2014,58（12）:7601⁃7605. doi: 10.1128/AAC. 04134⁃14.
［7］	Shields RK, Nguyen MH, Press EG, et al. The presence of an FKS mutation rather than MIC is an independent risk factor for failure of echinocandin therapy among patients with invasive candidiasis due to Candida glabrata［J］. Antimicrob Agents Chemother, 2012,56（9）:4862⁃4869. doi: 10.1128/AAC.00027⁃12.
［8］	Perlin DS. Mechanisms of echinocandin antifungal drug resistance［J］. Ann N Y Acad Sci, 2015,1354（1）:1⁃11. doi: 10. 1111/nyas.12831.
［9］	Pristov KE, Ghannoum MA. Resistance of Candida to azoles and echinocandins worldwide［J］. Clin Microbiol Infect, 2019,25（7）:792⁃798. doi: 10.1016/j.cmi.2019.03.028.
［10］	Bowman SM, Free SJ. The structure and synthesis of the fungal cell wall［J］. Bioessays, 2006,28（8）:799⁃808. doi: 10.1002/bies.20441.
［11］	Lee KK, Kubo K, Abdelaziz JA, et al. Yeast species⁃specific,differential inhibition of β⁃1,3⁃glucan synthesis by poacic acid and caspofungin［J］. Cell Surf, 2018,3:12⁃25. doi: 10.1016/j.tcsw.2018.09.001.
［12］	Antinori S, Milazzo L, Sollima S, et al. Candidemia and invasive candidiasis in adults: a narrative review［J］. Eur J Intern Med, 2016,34:21⁃28. doi: 10.1016/j.ejim.2016.06.029.
［13］	Lim HJ, Shin JH, Kim MN, et al. Evaluation of two commercial broth microdilution methods using different interpretive criteria for the detection of molecular mechanisms of acquired azole and echinocandin resistance in four common Candida species［J］. Antimicrob Agents Chemother, 2020,64（11）:e00740⁃20. doi: 10.1128/AAC.00740⁃20.
［14］	Spettel K, Barousch W, Makristathis A, et al. Analysis of antifungal resistance genes in Candida albicans and Candida glabrata using next generation sequencing［J/OL］. PLoS One, 2019,14（1）:e0210397［2021⁃01⁃05］. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328131/. doi: 10.1371/journal.pone.0210397.
［15］	Garcia⁃Effron G, Park S, Perlin DS. Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints［J］. Antimicrob Agents Chemother, 2009,53（1）:112⁃122. doi: 10. 1128/AAC.01162⁃08.
［16］	Logan C, Martin⁃Loeches I, Bicanic T. Invasive candidiasis in critical care: challenges and future directions［J］. Intensive Care Med, 2020,46（11）:2001⁃2014. doi: 10.1007/s00134⁃020⁃06240⁃x.
［17］	Sitterlé E, Coste AT, Obadia T, et al. Large⁃scale genome mining allows identification of neutral polymorphisms and novel resistance mutations in genes involved in Candida albicans resistance to azoles and echinocandins［J］. J Antimicrob Chemother, 2020,75（4）: 835⁃848. doi: 10.1093/jac/dkz537.
［18］	Arendrup MC, Park S, Brown S, et al. Evaluation of CLSI M44⁃A2 disk diffusion and associated breakpoint testing of caspofungin and micafungin using a well⁃characterized panel of wild⁃type and fks hot spot mutant Candida isolates［J］. Antimicrob Agents Chemother, 2011,55（5）:1891⁃1895. doi: 10. 1128/AAC.01373⁃10.
［19］	Cheung YY, Hui M. Effects of Echinocandins in combination with nikkomycin Z against invasive Candida albicans bloodstream isolates and the FKS mutants［J］. Antimicrob Agents Chemother, 2017,61（11）: e00619⁃17. doi: 10.1128/AAC. 00619⁃17.
［20］	Shields RK, Nguyen MH, Press EG, et al. Rate of FKS mutations among consecutive Candida isolates causing bloodstream infection［J］. Antimicrob Agents Chemother, 2015,59（12）:7465⁃7470. doi: 10.1128/AAC.01973⁃15.
［21］	Sanguinetti M, Posteraro B, Lass⁃Flörl C. Antifungal drug resistance among Candida species: mechanisms and clinical impact［J］. Mycoses, 2015,58（S2）:2⁃13. doi: 10.1111/myc.12330.
［22］	Forche A, Abbey D, Pisithkul T, et al. Stress alters rates and types of loss of heterozygosity in Candida albicans［J］. mBio, 2011,2（4）: e00129⁃11. doi: 10.1128/mBio.00129⁃11.
［23］	Suwunnakorn S, Wakabayashi H, Kordalewska M, et al. FKS2 and FKS3 genes of opportunistic human pathogen Candida albicans influence echinocandin susceptibility［J］. Antimicrob Agents Chemother, 2018,62（4）:e02299⁃17. doi: 10.1128/AAC. 02299⁃17.
［24］	Katiyar SK, Alastruey⁃Izquierdo A, Healey KR, et al. Fks1 and Fks2 are functionally redundant but differentially regulated in Candida glabrata: implications for echinocandin resistance［J］. Antimicrob Agents Chemother, 2012,56（12）:6304⁃6309. doi: 10. 1128/AAC.00813⁃12.
［25］	Healey KR, Zhao Y, Perez WB, et al. Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi⁃drug resistance［J］. Nat Commun, 2016,7:11128. doi: 10.1038/ncomms11128.
［26］	Rybak JM, Dickens CM, Parker JE, et al. Loss of C⁃5 sterol desaturase activity results in increased resistance to azole and echinocandin antifungals in a clinical isolate of Candida parapsilosis［J］. Antimicrob Agents Chemother, 2017,61（9）:e00651⁃17. doi: 10.1128/AAC.00651⁃17.
［27］	Niimi K, Maki K, Ikeda F, et al. Overexpression of Candida albicans CDR1, CDR2, or MDR1 does not produce significant changes in echinocandin susceptibility［J］. Antimicrob Agents Chemother, 2006,50（4）:1148⁃1155. doi: 10.1128/AAC.50.4.1148⁃ 1155.2006.
［28］	Pfaller MA, Castanheira M, Lockhart SR, et al. Frequency of decreased susceptibility and resistance to echinocandins among fluconazole⁃resistant bloodstream isolates of Candida glabrata［J］. J Clin Microbiol, 2012,50（4）:1199⁃1203. doi: 10.1128/JCM. 06112⁃11.
［29］	Vediyappan G, Rossignol T, d′Enfert C. Interaction of Candida albicans biofilms with antifungals: transcriptional response and binding of antifungals to beta⁃glucans［J］. Antimicrob Agents Chemother, 2010,54（5）:2096⁃2111. doi: 10.1128/AAC.01638⁃09.
［30］	Shor E, Perlin DS. Coping with stress and the emergence of multidrug resistance in fungi［J/OL］. PLoS Pathog, 2015,11（3）:e1004668［2021⁃01⁃10］. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366371/. doi: 10.1371/journal.ppat.1004668.
［31］	Accoceberry I, Couzigou C, Fitton⁃Ouhabi V, et al. Challenging SNP impact on caspofungin resistance by full⁃length FKS1 allele replacement in Candida lusitaniae［J］. J Antimicrob Chemother, 2019,74（3）:618⁃624. doi: 10.1093/jac/dky475.
［32］	Healey KR, Katiyar SK, Raj S, et al. CRS⁃MIS in Candida glabrata: sphingolipids modulate echinocandin⁃Fks interaction［J］. Mol Microbiol, 2012,86（2）:303⁃313. doi: 10.1111/j.1365⁃2958.2012.08194.x.
［33］	Garnaud C, García⁃Oliver E, Wang Y, et al. The rim pathway mediates antifungal tolerance in Candida albicans through newly identified Rim101 transcriptional targets, including Hsp90 and Ipt1［J］. Antimicrob Agents Chemother, 2018,62（3）:e01785⁃17. doi: 10.1128/AAC.01785⁃17.
［34］	Gonzalez⁃Lara MF, Ostrosky⁃Zeichner L. Invasive candidiasis［J］. Semin Respir Crit Care Med, 2020,41（1）:3⁃12. doi: 10. 1055/s⁃0040⁃1701215.

[1]	张瑞珺苏小睿李婷何肖杨元文康玉英. 山西省某三甲医院黏膜念珠菌病病原菌和耐药性分析[J]. 中华皮肤科杂志, 2023, 56(1): 56-58.
[2]	陈玉萍郑海林张之烽梅嬛刘维达刘沐桑. 南京某医院201株烟曲霉感染患者临床资料与唑类耐药情况回顾性分析[J]. 中华皮肤科杂志, 2022, 55(4): 316-320.
[3]	欧敏, 颜韵灵, 郑宝庆, 王晓华. 银屑病与肥胖相关性的研究进展[J]. 中华皮肤科杂志, 2022, 55(2): 181-184.
[4]	王佳绮, 王平, 李刘雨, 樊奇敏, 朱蒙燕, 王燕清, 周鸿宇, 沈宏, 许爱娥. 皮肤色素减退性淋巴增殖性疾病41例临床病理分析[J]. 中华皮肤科杂志, 2022, 55(2): 110-115.
[5]	林羽洁, 刘凤洁, 高玉梅, 刘向君, 许卜方, 李映依, 赖盼, 陈卓婧, 孙婧茹, 涂平, 汪旸. 溶血磷脂酸受体6在蕈样肉芽肿向大细胞转变中的意义及其对皮肤T细胞淋巴瘤细胞增殖和凋亡的影响[J]. 中华皮肤科杂志, 2022, 55(2): 102-109.
[6]	陈绍椿刘经纬周可尹跃平. 头孢曲松耐药淋病奈瑟菌株FC428的流行、耐药机制及应对策略[J]. 中华皮肤科杂志, 2022, 55(12): 1122-1126.
[7]	丁甜甜崔宝红米淑宏张杨郑海林石继海刘维达. 浅部与深部感染来源白念珠菌氟康唑耐药株药物敏感性及耐药基因突变比较[J]. 中华皮肤科杂志, 2022, 55(10): 874-878.
[8]	田翠翠陈浩. 皮肤T细胞淋巴瘤瘙痒发病机制研究进展[J]. 中华皮肤科杂志, 2022, 0(1): 20210941-e20210941.
[9]	杨瑞孔庆涛许洁张晨桑红. 复发性念珠菌颈部淋巴结炎1例易感基因筛查及免疫学研究[J]. 中华皮肤科杂志, 2022, 55(1): 50-54.
[10]	张莹甘璐李思琪李颜宋昊邵雪宝张韡徐秀莲姜祎群曾学思陈浩孙建方. 伴大细胞转化的蕈样肉芽肿24例临床病理及免疫表型分析[J]. 中华皮肤科杂志, 2022, 55(1): 20-26.
[11]	李海洋林尽染刘庆梅倪春雅吴文育. 微生物群与头皮毛发疾病相关性研究进展[J]. 中华皮肤科杂志, 2022, 0(1): 20201196-e20201196.
[12]	孔雪史冬梅刘维达. 抗真菌药在特殊人群的应用[J]. 中华皮肤科杂志, 2022, 55(1): 80-83.
[13]	罗宏潘开素张莲谈园黄敖曹存巍. 小檗碱体外对酵母相马尔尼菲篮状菌的抗菌活性检测[J]. 中华皮肤科杂志, 2022, 55(1): 55-57.
[14]	李婷婷关猛猛赵娟康晓静. 单细胞转录组测序在黑素瘤研究中的应用[J]. 中华皮肤科杂志, 2022, 0(1): 20210191-e20210191.
[15]	林泽杭段志敏徐松陈旭李岷. 白念珠菌菌丝调控小鼠巨噬细胞自噬关键分子微管相关蛋白1轻链3的实验研究[J]. 中华皮肤科杂志, 2021, 54(3): 189-195.

白念珠菌对棘白菌素类药物耐药机制的研究进展

Mechanisms underlying the resistance of Candida albicans to echinocandin antifungals

PDF

PDF (Mobile)

可视化

摘要/Abstract

引用本文

使用本文

参考文献 34

相关文章 15

Metrics

本文评价

推荐阅读 10