新型隐球菌耐药性和药物耐受性检测及其机制研究进展

doi:10.3969/j.issn.1673-8640.2024.12.002

摘要/Abstract

摘要：

新型隐球菌是全球分布的机会性真菌病原体，引起的隐球菌脑膜炎是获得性免疫缺陷综合征患者死亡的重要因素之一。目前，抗真菌治疗药物的种类有限，一定程度上加剧了新型隐球菌的耐药性和药物耐受性。在一些病例中，即使用体外药物敏感性试验结果提示敏感的药物进行治疗，病情依然迁延不愈或复发。这可能与药物耐受性有关。药物耐受性的发现，反映了更为复杂的抗真菌药物耐药机制。了解新型隐球菌耐药性和药物耐受性及其机制至关重要，可为制定临床治疗方案和开发新型抗真菌药物提供思路。

关键词: 新型隐球菌, 耐药, 药物耐受

Abstract:

Cryptococcus neoformans is a globally distributed opportunistic fungal pathogen，which causes cryptococcal meningitis，a factor in the mortality of acquired immune deficiency syndrome patients. At present，the kinds of antifungal drugs are limited，which causes in drug resistance and tolerance to Cryptococcus neoformans. In some cases，even if the in vitro drug susceptibility test suggests sensitivity，the treatment with the drug is still prolonged or relapses. This may be associated with drug tolerance. The discovery of drug tolerance responds to more complex mechanisms of antifungal drug resistance. Understanding the drug resistance and tolerance to Cryptococcus neoformans as well as the mechanisms is critical，which can provide ideas for clinical treatment regimen design and the development of new antifungal drugs.

Key words: Cryptococcus neoformans, Drug resistance, Drug tolerance

中图分类号:

R446.1

王子文, 吴文娟. 新型隐球菌耐药性和药物耐受性检测及其机制研究进展[J]. 检验医学, 2024, 39(12): 1140-1144.

WANG Ziwen, WU Wenjuan. Research progress on determination and mechanism of drug resistance and tolerance to Cryptococcus neoformans[J]. Laboratory Medicine, 2024, 39(12): 1140-1144.

参考文献 47

[1]	ZHAO Y, YE L, ZHAO F, et al. Cryptococcus neoformans,a global threat to human health[J]. Infect Dis Poverty, 2023, 12(1):20.
[2]	IYER K R, REVIE N M, FU C, et al. Treatment strategies for cryptococcal infection:challenges,advances and future outlook[J]. Nat Rev Microbiol, 2021, 19(7):454-466.
[3]	FISHER M C, HAWKINS N J, SANGLARD D, et al. Worldwide emergence of resistance to antifungal drugs challenges human health and food security[J]. Science, 2018, 360(6390):739-742. DOI PMID
[4]	World Health Organization(WHO). WHO fungal priority pathogens list to guide research,development and public health action[EB/OL].(2022-10-25)[2023-12-31]. https://www.who.int/publications/i/item/9789240060241.
[5]	PERFECT J R, DISMUKES W E, DROMER F, et al. Clinical practice guidelines for the management of cryptococcal disease:2010 update by the infectious diseases society of America[J]. Clin Infect Dis, 2010, 50(3):291-322.
[6]	CHEN L, ZHANG L, XIE Y, et al. Confronting antifungal resistance,tolerance,and persistence:advances in drug target discovery and delivery systems[J]. Adv Drug Deliv Rev, 2023,200:115007.
[7]	BERMAN J, KRYSAN D J. Drug resistance and tolerance in fungi[J]. Nat Rev Microbiol, 2020, 18(9):539.
[8]	YANG J H, HUANG P Y, CHENG C W, et al. Antifungal susceptibility testing with YeastONE™ is not predictive of clinical outcomes of Cryptococcus neoformans var. grubii fungemia[J]. Med Mycol, 2021, 59(11):1114-1121.
[9]	Clinical and Laboratory Standards Institute. Epidemiological cutoff values for antifungal susceptibility testing[S]. M57S,CLSI, 2022.
[10]	European Committee on Antimicrobial Susceptibility Testing. Overview of antifungal ECOFFs and clinical breakpoints for yeasts,moulds and dermatophytes using the EUCAST E.Def 7.4,E.Def 9.4 and E.Def 11.0 procedures[S]. EUCAST, 2023.
[11]	范欣, 肖盟, 王贺, 等. 新型隐球菌显色微量肉汤稀释法药敏流行病学折点的建立[J]. 中华医院感染学杂志, 2016, 26(10):2215-2218.
[12]	樊红丽, 高丽, 杨翠先, 等. 云南省新型隐球菌药物敏感流行病学折点的建立[J]. 重庆医学, 2019, 48(18):3188-3190.
[13]	ARENDRUP M C, PATTERSON T F. Multidrug-resistant Candida:epidemiology,molecular mechanisms,and treatment[J]. J Infect Dis, 2017, 216(suppl 3):S445-S451.
[14]	THOMPSON J R, DOUGLAS C M, LI W, et al. A glucan synthase FKS1 homolog in Cryptococcus neoformans is single copy and encodes an essential function[J]. J Bacteriol, 1999, 181(2):444-453.
[15]	ROBBINS N, CAPLAN T, COWEN L E. Molecular evolution of antifungal drug resistance[J]. Annu Rev Microbiol, 2017,71:753-775.
[16]	RODERO L, MELLADO E, RODRIGUEZ A C, et al. G484S amino acid substitution in lanosterol 14-alpha demethylase(ERG11) is related to fluconazole resistance in a recurrent Cryptococcus neoformans clinical isolate[J]. Antimicrob Agents Chemother, 2003, 47(11):3653-3656.
[17]	SIONOV E, CHANG Y C, GARRAFFO H M, et al. Identification of a Cryptococcus neoformans cytochrome P450 lanosterol 14α-demethylase(Erg11)residue critical for differential susceptibility between fluconazole/voriconazole and itraconazole/posaconazole[J]. Antimicrob Agents Chemother, 2012, 56(3):1162-1169.
[18]	ATIM P B, MEYA D B, GERLACH E S, et al. Lack of association between fluconazole susceptibility and ERG11 nucleotide polymorphisms in Cryptococcus neoformans clinical isolates from Uganda[J]. J Fungi(Basel), 2022, 8(5):508.
[19]	SELB R, FUCHS V, GRAF B, et al. Molecular typing and in vitro resistance of Cryptococcus neoformans clinical isolates obtained in Germany between 2011 and 2017[J]. Int J Med Microbiol, 2019, 309(6):151336.
[20]	KELLY S L, LAMB D C, TAYLOR M, et al. Resistance to amphotericin B associated with defective sterol delta 8-->7 isomerase in a Cryptococcus neoformans strain from an AIDS patient[J]. FEMS Microbiol Lett, 1994, 122(1-2):39-42.
[21]	LOYSE A, DROMER F, DAY J, et al. Flucytosine and cryptococcosis:time to urgently address the worldwide accessibility of a 50-year-old antifungal[J]. J Antimicrob Chemother, 2013, 68(11):2435-2444.
[22]	HOPE W W, TABERNERO L, DENNING D W, et al. Molecular mechanisms of primary resistance to flucytosine in Candida albicans[J]. Antimicrob Agents Chemother, 2004, 48(11):4377-4386.
[23]	BILLMYRE R B, APPLEN CLANCEY S, LI L X, et al. 5-Fluorocytosine resistance is associated with hypermutation and alterations in capsule biosynthesis in Cryptococcus[J]. Nat Commun, 2020, 11(1):127.
[24]	CHANG Y C, LAMICHHANE A K, CAI H, et al. Moderate levels of 5-fluorocytosine cause the emergence of high frequency resistance in Cryptococci[J]. Nat Commun, 2021, 12(1):3418.
[25]	FISHER M C, ALASTRUEY-IZQUIERDO A, BERMAN J, et al. Tackling the emerging threat of antifungal resistance to human health[J]. Nat Rev Microbiol, 2022, 20(9):557-571. DOI PMID
[26]	GUSA A, WILLIAMS J D, CHO J E, et al. Transposon mobilization in the human fungal pathogen Cryptococcus is mutagenic during infection and promotes drug resistance in vitro[J]. Proc Natl Acad Sci U S A, 2020, 117(18):9973-9980.
[27]	BOYCE K J, WANG Y, VERMA S, et al. Mismatch repair of DNA replication errors contributes to microevolution in the pathogenic fungus Cryptococcus neoformans[J]. mBio, 2017, 8(3):e00595-17.
[28]	POSTERARO B, SANGUINETTI M, SANGLARD D, et al. Identification and characterization of a Cryptococcus neoformans ATP binding cassette(ABC) transporter-encoding gene,CnAFR1,involved in the resistance to fluconazole[J]. Mol Microbiol, 2003, 47(2):357-371.
[29]	CHANG M, SIONOV E, KHANAL LAMICHHANE A, et al. Roles of three Cryptococcus neoformans and Cryptococcus gattii efflux pump-coding genes in response to drug treatment[J]. Antimicrob Agents Chemother, 2018, 62(4):e01751-17.
[30]	WHELAN W L. The genetic basis of resistance to 5-fluorocytosine in Candida species and Cryptococcus neoformans[J]. Crit Rev Microbiol, 1987, 15(1):45-56.
[31]	CHANG Z, YADAV V, LEE S C, et al. Epigenetic mechanisms of drug resistance in fungi[J]. Fungal Genet Biol, 2019,132:103253.
[32]	JANBON G, MAENG S, YANG D H, et al. Characterizing the role of RNA silencing components in Cryptococcus neoformans[J]. Fungal Genet Biol, 2010, 47(12):1070-1080.
[33]	PRIEST S J, YADAV V, ROTH C, et al. Uncontrolled transposition following RNAi loss causes hypermutation and antifungal drug resistance in clinical isolates of Cryptococcus neoformans[J]. Nat Microbiol, 2022, 7(8):1239-1251.
[34]	SHELEST E. Transcription factors in fungi[J]. FEMS Microbiol Lett, 2008, 286(2):145-151. DOI PMID
[35]	SONG M H, LEE J W, KIM M S, et al. A flucytosine-responsive Mbp1/Swi4-like protein,Mbs1,plays pleiotropic roles in antifungal drug resistance,stress response,and virulence of Cryptococcus neoformans[J]. Eukaryot Cell, 2012, 11(1):53-67.
[36]	CHUN C D, LIU O W, MADHANI H D. A link between virulence and homeostatic responses to hypoxia during infection by the human fungal pathogen Cryptococcus neoformans[J]. PLoS Pathog, 2007, 3(2):e22.
[37]	CHANG Y C, BIEN C M, LEE H, et al. Sre1p,a regulator of oxygen sensing and sterol homeostasis,is required for virulence in Cryptococcus neoformans[J]. Mol Microbiol, 2007, 64(3):614-629.
[38]	JUNG K W, YANG D H, MAENG S, et al. Systematic functional profiling of transcription factor networks in Cryptococcus neoformans[J]. Nat Commun, 2015,6:6757.
[39]	PAUL S, DOERING T L, MOYE-ROWLEY W S. Cryptococcus neoformans Yap1 is required for normal fluconazole and oxidative stress resistance[J]. Fungal Genet Biol, 2015,74:1-9.
[40]	SIONOV E, LEE H, CHANG Y C, et al. Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes[J]. PLoS Pathog, 2010, 6(4):e1000848.
[41]	NGAMSKULRUNGROJ P, CHANG Y, HANSEN B, et al. Characterization of the chromosome 4 genes that affect fluconazole-induced disomy formation in Cryptococcus neoformans[J]. PLoS One, 2012, 7(3):e33022.
[42]	TSAI H J, NELLIAT A. A double-edged sword:aneuploidy is a prevalent strategy in fungal adaptation[J]. Genes(Basel), 2019, 10(10):787.
[43]	ROSENBERG A, ENE I V, BIBI M, et al. Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia[J]. Nat Commun, 2018, 9(1):2470. DOI PMID
[44]	BHATTACHARYA S, HOLOWKA T, ORNER E P, et al. Gene duplication associated with increased fluconazole tolerance in Candida auris cells of advanced generational age[J]. Sci Rep, 2019, 9(1):5052.
[45]	KIM S H, IYER K R, PARDESHI L, et al. Genetic analysis of Candida auris implicates Hsp90 in morphogenesis and azole tolerance and Cdr1 in azole resistance[J]. mBio, 2019, 10(1):e02529-18.
[46]	COWEN L E. Hsp90 orchestrates stress response signaling governing fungal drug resistance[J]. PLoS Pathog, 2009, 5(8):e1000471.
[47]	LEVIN-REISMAN I, RONIN I, GEFEN O, et al. Antibiotic tolerance facilitates the evolution of resistance[J]. Science, 2017, 355(6327):826-830.