唑类抗真菌药物临床耐药性研究进展

Research Progress on Clinical Drug Resistance of Azole Antifungal Agents

摘要

随着唑类抗真菌药物在临床的广泛应用，其真菌耐药性问题日益突出，已成为制约真菌感染治疗效果的关键挑战。综述系统梳理了唑类抗真菌药物耐药机制的研究进展，重点阐述了药物靶标甾醇14α-去甲基化酶突变与过表达、ATP结合盒超家族转运蛋白/主要协助转运超家族转运蛋白外排泵激活、细胞膜重塑及代谢通路重编程4大核心耐药机制；全面总结了当前应对真菌耐药的主要策略，包括老药新用、分子结构优化、靶向给药系统开发及基于机制的联合用药方案；并分类介绍了已上市、临床试验阶段及临床前研究中的抗耐药唑类药物，重点分析了新型唑类衍生物的抗耐药优势与应用前景。旨在为临床合理选择抗真菌药物、优化耐药感染治疗方案提供参考，同时为新型抗耐药唑类药物的研发方向提供思路与理论依据。

Abstract

With the widespread clinical application of azole antifungal agents, fungal drug resistance has become increasingly prominent, emerging as a critical challenge restricting the therapeutic efficacy of fungal infection therapy. This review systematically summarizes the research progress on the resistance mechanisms of azole antifungal agents, focusing on four core resistance mechanisms: mutations and overexpression of the drug target sterol 14α-demethylase, activation of ATP-binding cassette superfamily transporters/major facilitator superfamily transporter efflux pumps, cell membrane remodeling, and metabolic pathway reprogramming. It comprehensively outlines the current main strategies for combating fungal resistance, including drug repurposing, molecular structure optimization, development of targeted drug delivery systems, and mechanism-based combination therapy regimens. Furthermore, it categorically introduces anti-resistant azole drugs that are already on the market, in clinical trials, and in preclinical research, with a focus on analyzing the anti-resistance advantages and application prospects of novel azole derivatives. This review aims to provide references for the rational clinical selection of antifungal agents and the optimization of treatment regimens for resistant infections, as well as to offer insights and theoretical bases for the research and development of novel anti-resistant azole drugs.

关键词

唑类 / 抗真菌药物 / 真菌耐药性 / 耐药机制

Key words

azoles / antifungal agents / fungal drug resistance / drug resistance mechanisms

参考文献

[1] Bouz G, Doležal M. Advances in antifungal drug development: an up—to—date mini review[J].Pharmaceuticals (Basel), 2021, 14(12): 1312.

[2] Boral H, Metin B, Döğen A, et al. Overview of selected virulence attributes in Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, Trichophyton rubrum, and Exophiala dermatitidis[J].Fungal Genet Biol, 2018, 111: 92-107.

[3] Wei J, Zhu L, Lu Q, et al. Recent progress and applications of poly(beta amino esters)—based biomaterials[J].J Control Release, 2023, 354: 337-353.

[4] Kainz K, Bauer M A, Madeo F, et al. Fungal infections in humans: the silent crisis[J].Microb Cell, 2020, 7(6): 143-145.

[5] Mehta D, Saini V, Bajaj A. Recent developments in membrane targeting antifungal agents to mitigate antifungal resistance[J].RSC Med Chem, 2023, 14(9): 1603-1628.

[6] Riddell N, Jin U H, Safe S, et al. Characterization and biological potency of mono— to tetra—halogenated carbazoles[J].Environ Sci Technol, 2015, 49(17): 10658-10666.

[7] Heidari A, Sharma R, Shakir Q, et al. Isavuconazole in the treatment of chronic forms of coccidioidomycosis[J].Clin Infect Dis, 2023, 76(12): 2196-2199.

[8] Tumietto F, Posteraro B, Sanguinetti M. Looking for appropriateness in the cure of mixed vaginitis: the role of fenticonazole as an empiric treatment[J].Future Microbiol, 2019, 14(16): 1349-1355.

[9] Otu A, Bongomin F, Kosmidis C, et al. Acute kidney injury: an unusual complication of posaconazole use[J].J Chemother, 2018, 30(6/7/8): 380-383.

[10] Ivanov M, Ćirić A, Stojković D. Emerging antifungal targets and strategies[J].Int J Mol Sci, 2022, 23(5): 2756.

[11] Ahmed S, Amin M M, El—Korany S M, et al. Corneal targeted fenticonazole nitrate—loaded novasomes for the management of ocular candidiasis: preparation, in vitro characterization, ex vivo and in vivo assessments[J].Drug Deliv, 2022, 29(1): 2428-2441.

[12] Yadav D, Baidya P, Panday P R, et al. Fluconazole—resistant vulvovaginal candidiasis in reproductive—age women: a study from Himalayan country[J].BMC Microbiol, 2025, 25(1): 656.

[13] Girmenia C, Venditti M, Martino P. Fluconazole in combination with flucytosine in the treatment of fluconazole—resistant Candida infections[J].Diagn Microbiol Infect Dis, 2003, 46(3): 227-231.

[14] Meireles L M, Soares F S, de Souza Filho G A, et al. Exposure to tebuconazole drives cross—resistance to clinical triazoles in Aspergillus fumigatus[J].ACS Omega, 2025, 10(42): 50407-50414.

[15] Li S S, Tang X Y, Zhang S G, et al. Voriconazole combined with low—dose amphotericin B liposome for treatment of cryptococcal meningitis[J].Infect Dis (Lond), 2016, 48(7): 563-565.

[16] 李彤, 卢芳国. 烟曲霉耐药机制及中药单体干预作用的研究进展[J].中国病原生物学杂志, 2023, 18(7): 848-853.

[17] Chen S, Sun K Y, Feng X W, et al. Efficacy and safety of itraconazole use in infants[J].World J Pediatr, 2016, 12(4): 399-407.

[18] Yenişehirli G, Alıcı A, Yenişehirli A. Antifungal drug susceptibility profiles and molecular mechanisms of azole resistance in Candida blood stream isolates[J].Indian J Med Microbiol, 2023, 45: 100389.

[19] 谭静文, 高志琴, 杨虹, 等. 国产泊沙康唑对生殖器来源念珠菌的体外药物敏感性研究[J].中国真菌学杂志, 2021, 16(5): 326—329, 334.

[20] Kawasaki A, Shintani R, Takao R, et al. Efficacy and safety of isavuconazole for invasive fungal infections: a systematic review and meta—analysis of randomized controlled trials[J].Med Mycol, 2025, 63(10): myaf089.

[21] Ullah N, Sepulcri C, Mikulska M. Isavuconazole for COVID—19—associated invasive mold infections[J].J Fungi (Basel), 2022, 8(7): 674.

[22] Darnaud L, Lamoureux F, Godet C, et al. Isavuconazole kinetic exploration for clinical practice[J].Drugs R D, 2018, 18(4): 317-321.

[23] Vandecruys P, Baldewijns S, Sillen M, et al. Oteseconazole: a long—awaited diversification of the antifungal arsenal to manage recurrent vulvovaginal candidiasis (RVVC)[J].Expert Rev Anti Infect Ther, 2023, 21(8): 799-812.

[24] 韩晓燕, 宋亚丽, 白埔, 等. 抗真菌药物的系统分类、耐药机制及新药研发进展[J].中国现代应用药学, 2019, 36(11): 1430-1436.

[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.

[26] Shibata T, Takahashi T, Yamada E, et al. T—2307 causes collapse of mitochondrial membrane potential in yeast[J].Antimicrob Agents Chemother, 2012, 56(11): 5892-5897.

[27] Hoy S M. Oteseconazole: first approval[J].Drugs, 2022, 82(9): 1017-1023.

[28] Salci T P, Negri M, Abadio A K R, et al. Targeting Candida spp. to develop antifungal agents[J].Drug Discov Today, 2018, 23(4): 802-814.

[29] Kan S, Tan J, Cai Q, et al. Synergistic activity of the combination of falcarindiol and itraconazole in vitro against dermatophytes[J].Front Cell Infect Microbiol, 2023, 13: 1128000.

[30] Hervay N T, Elias D, Habova M, et al. Catechin potentiates the antifungal effect of miconazole in Candida glabrata[J].Folia Microbiol(Praha), 2023, 68(6): 835-842.

[31] Denardi L B, Keller J T, Oliveira V, et al. Activity of combined antifungal agents against multidrug—resistant Candida glabrata strains[J].Mycopathologia, 2017, 182(9/10): 819-828.

[32] Fakhim H, Chowdhary A, Prakash A, et al. In vitro interactions of echinocandins with triazoles against multidrug—resistant Candida auris[J].Antimicrob Agents Chemother, 2017, 61(11): e01056—17.

[33] Shiva Kumar K, Adepu R, Sandra S, et al. Cu—mediated N—arylation of 1, 2, 3—triazin—4—ones: synthesis of fused triazinone derivatives as potential inhibitors of chorismate mutase[J].Bioorg Med Chem Lett, 2012, 22(2): 1146-1150.

[34] World Health Organization. Guidelines for the diagnosis, prevention and management of cryptococcal disease in HIV—infected adults, adolescents and children [S]. Geneva:World Health Organization, 2018.

[35] Vanreppelen G, Nysten J, Baldewijns S, et al. Oteseconazole (VIVOJA) for prevention of recurrent vulvovaginal candidiasis[J].Trends Pharmacol Sci, 2023, 44(1): 64-65.

[36] 江英骙, 朱利平. 新型抗真菌药艾沙康唑的研究进展[J].药学进展, 2021, 45(6): 427-432.

[37] Ito K, Kizawa Y, Kimura G, et al. Relationship between antifungal effects and lung exposure of PC945, a novel inhaled antifungal agent, in Aspergillus fumigatus infected mice: pulmonary PK—PD analysis of anti—fungal PC945[J].Eur J Pharm Sci, 2021, 163: 105878.

[38] Jacobs S E, Zagaliotis P, Walsh T J. Novel antifungal agents in clinical trials[J].F1000Res, 2021, 10: 507.

[39] Colley T, Alanio A, Kelly S L, et al. In vitro and in vivo antifungal profile of a novel and long—acting inhaled azole, PC945, on Aspergillus fumigatus infection[J].Antimicrob Agents Chemother, 2017, 61(5): e02280—16.

[40] Wu P, Zhang J, Meng Q, et al. Novel pyrrolobenzoxaboroles: design, synthesis, and biological evaluation against Trypanosoma brucei[J].Eur J Med Chem, 2014, 81: 59-75.

[41] Zhang J, Yang F, Qiao Z, et al. Chalcone—benzoxaborole hybrids as novel anticancer agents[J].Bioorg Med Chem Lett, 2016, 26(23): 5797-5801.

[42] Yan Z Z, Lv Z B, Zhao D Z, et al. Design, synthesis, and biological evaluation of novel boron—containing azoles as potential antifungal agents[J].J Mol Struct, 2023, 1291: 135997.

[43] Frieben E E, Amin, Sharma A K. Development of isoselenocyanate compounds' syntheses and biological applications[J].J Med Chem, 2019, 62(11): 5261-5275.

[44] Xu H, Yan Z Z, Guo M B, et al. Lead optimization generates selenium—containing miconazole CYP51 inhibitors with improved pharmacological profile for the treatment of fungal infections[J].Eur J Med Chem, 2021, 216: 113337.

[45] Ji C, Liu N, Tu J, et al. Drug repurposing of haloperidol: discovery of new benzocyclane derivatives as potent antifungal agents against cryptococcosis and candidiasis[J].ACS Infect Dis, 2020, 6(5): 768-786.

[46] Chi X, Xie F, Li L, et al. Discovery of novel triazoles containing benzyloxy phenyl isoxazole side chain with potent and broad—spectrum antifungal activity[J].Bioorg Chem, 2023, 137: 106572.

[47] Boyer J, Feys S, Zsifkovits I, et al. Treatment of invasive aspergillosis: how it’s going, where it’s heading[J].Mycopathologia, 2023, 188(5): 667-681.

[48] Ding Z, Ni T, Xie F, et al. Design, synthesis, and structure—activity relationship studies of novel triazole agents with strong antifungal activity against Aspergillus fumigatus[J].Bioorg Med Chem Lett, 2020, 30(4): 126951.

[49] Turky A, Bayoumi A H, Sherbiny F F, et al. Unravelling the anticancer potency of 1, 2, 4—triazole—N—arylamide hybrids through inhibition of STAT3: synthesis and in silico mechanistic studies[J].Mol Divers, 2021, 25(1): 403-420.

[50] Sadeghian S, Emami L, Mojaddami A, et al. 1, 2, 4—Triazole derivatives as novel and potent antifungal agents: design, synthesis and biological evaluation[J].J Mol Struct, 2023, 1271: 134039.

[51] Xie F, Hao Y, Bao J, et al. Design, synthesis, and in vitro evaluation of novel antifungal triazoles containing substituted 1, 2, 3—triazole—methoxyl side chains[J].Bioorg Chem, 2022, 129: 106216.

[52] Li Z, Liu N, Yang W, et al. Controlling antifungal activity with light: optical regulation of fungal ergosterol biosynthetic pathway with photo—responsive CYP51 inhibitors[J].Acta Pharm Sin B, 2023, 13(7): 3080-3092.

[53] Jiang Y, Su L, Liao Y, et al. Synthesis and antifungal evaluation of phenol—derived bis(indolyl)methanes combined with FLC against Candida albicans[J].Bioorg Med Chem Lett, 2022, 58: 128525.

[54] Ma J, Jiang Y, Zhuang X, et al. Discovery of novel indole and indoline derivatives against Candida albicans as potent antifungal agents[J].Bioorg Med Chem Lett, 2022, 71: 128826.

[55] Chai N, Sun A, Zhu X, et al. Antifungal evaluation of quinoline—Chalcone derivatives combined with FLC against drug—resistant Candida albicans[J].Bioorg Med Chem Lett, 2023, 86: 129242.

[56] Sharma K, Parmanu P K, Sharma M. Mechanisms of antifungal resistance and developments in alternative strategies to combat Candida albicans infection[J].Arch Microbiol, 2024, 206(3): 95.

[57] Jansen A M E, Snijdelaar K, Keizer R J, et al. Personalized antifungal therapy through model—informed precision dosing of posaconazole[J].Clin Pharmacokinet, 2024, 63(5): 645-656.