Ekologiya cheloveka (Human Ecology)Ekologiya cheloveka (Human Ecology)Экология человека1728-08692949-1444Eco-Vector69545810.17816/humeco695458LXKNMCREVIEWSОБЗОРЫReview ArticleModern trends in the development of antifungal agentsСовременные тенденции в разработке противогрибковых препаратов抗真菌药物研发的当代趋势https://orcid.org/0000-0001-5098-53794409-8108AvtonomovaAnastasia V.АвтономоваАнастасия ВитальевнаAvtonomovaAnastasia V.
Russian Federation

Cand. Sci. (Biology)

канд. биол. наук

Cand. Sci. (Biology)

aavtonomova@cspfmba.ruhttps://orcid.org/0000-0003-4799-13181153-8414KisilOlga V.КисильОльга ВалерьевнаKisilOlga V.
Russian Federation

Cand. Sci. (Chemistry)

канд. хим. наук

Cand. Sci. (Chemistry)

olvv@mail.ruhttps://orcid.org/0000-0003-4772-96866642-7819ZagainovaAngelica V.ЗагайноваАнжелика ВладимировнаZagainovaAngelica V.
Russian Federation

Cand. Sci. (Biology)

канд. биол. наук

Cand. Sci. (Biology)

azagaynova@cspfmba.ruhttps://orcid.org/0000-0001-9495-02667842-8808MakarovValentin V.МакаровВалентин ВладимировичMakarovValentin V.
Russian Federation

Cand. Sci. (Biology)

канд. биол. наук

Cand. Sci. (Biology)

makarov@cspfmba.ruCentre for Strategic Planning and Management of Biomedical Health RiskЦентр стратегического планирования и управления медико-биологическими рисками здоровьюCentre for Strategic Planning and Management of Biomedical Health RiskGause Institute of New AntibioticsНаучно-исследовательский институт по изысканию новых антибиотиков имени Г.Ф. ГаузеGause Institute of New Antibiotics271120252212202532117637742910202511112025Copyright ©; 2025, Eco-VectorCopyright ©; 2025, Эко-ВекторCopyright ©; 2025, Eco-Vector2025Eco-VectorЭко-ВекторEco-Vectorhttps://creativecommons.org/licenses/by-nc-nd/4.0https://hum-ecol.ru/1728-0869/article/view/695458

Mycoses pose an increasing threat to public health, resulting in millions of invasive infections and a high mortality rate each year. The limited arsenal of antifungal agents, their toxicity, and the rapid spread of resistance underscore the urgent need for new therapeutic strategies. This review systematizes current trends in the development of antimycotic agents intended for the treatment of invasive mycoses. The primary focus is on drugs with novel mechanisms of action targeting key structures and metabolic pathways of the fungal cell. The emphasis is on publications from the past decade; however, significant fundamental research from earlier times has also been taken into account. The search was conducted in the electronic databases eLibrary.ru, PubMed, Google Scholar, and Wally. Promising approaches include inhibition of cell wall component synthesis, disruption of cell membrane function through effects on ergosterol, phospholipids, and sphingolipids, as well as effects on intracellular targets: fungal intracellular proteins and signaling pathways, protein biosynthesis processes, and nucleic acid replication and transcription. Agents inhibiting the synthesis of major cell wall components such as β-1,3-glucan (echinocandins, ibrexafungerpY), β-1,6-glucan, chitin (nikkomycin ZY), and GPI anchors (fosmanogepixY), are reviewed. Agents acting on ergosterol (oteseconazoleY, opelconazoleY), sphingolipids (IPC-synthase inhibitorsY), and phospholipids (mandimycinY) are analyzed. Fungal kinase inhibitors, Hsp90, calcineurin, N-myristoyltransferase, elongation factor EF-2, and nucleic acids (olorofimY) are described. Several of these compounds (olorofimY, fosmanogepixY, VT-1598Y, BSG005) are currently in clinical trials. The importance of identifying selective targets and developing combination therapy to overcome resistance and improve treatment effectiveness is emphasized.

Y Hereafter, it means that the medicinal product is not registered in the Russian Federation.

Микозы представляют растущую угрозу для общественного здоровья, ежегодно вызывая миллионы случаев инвазивных заболеваний и большое количество летальных исходов. Ограниченный арсенал противогрибковых препаратов, их токсичность и быстрое распространение резистентности диктуют острую необходимость в разработке новых терапевтических стратегий. Данный обзор систематизирует современные тенденции в создании антимикотиков, направленных на терапию инвазивных микозов. Основное внимание уделено препаратам с новыми механизмами действия, нацеленным на ключевые структуры и метаболические пути грибковой клетки. Акцент сделан на литературе последнего десятилетия, однако учтены и важные фундаментальные работы предыдущих периодов. Поиск проводили в электронных базах данных eLibrary.ru, PubMed, Google Scholar, Wally. Перспективными направлениями являются ингибирование синтеза компонентов клеточной стенки, нарушение функций клеточной мембраны через воздействие на эргостерол, фосфолипиды и сфинголипиды, а также влияние на внутриклеточные мишени: внутриклеточные белки и пути передачи сигналов в клетке гриба, процессы биосинтеза белка, процессы репликации и транскрипции нуклеиновых кислот. Рассматриваются ингибиторы синтеза основных компонентов клеточной стенки β-1,3-глюкана (эхинокандины, ибрексафунгерпY), β-1,6-глюкана, хитина (никкомицин Z) и GPI-якорей (фосманогепиксY). Анализируются препараты, воздействующие на эргостерол (отесеконазолY, опельконазолY), сфинголипиды (ингибиторы IPC-синтазы) и фосфолипиды (мандимицинY). Описаны ингибиторы грибковых киназ, Hsp90, кальциневрина, N-миристоилтрансферазы, фактора элонгации EF-2 и нуклеиновых кислот (олорофимY). Некоторые из этих соединений (олорофимY, фосманогепиксY, VT-1598Y, BSG005) находятся на стадии клинических исследований. Подчёркивается важность поиска селективных мишеней и разработки комбинированной терапии для преодоления резистентности и повышения эффективности лечения.

Y Здесь и далее означает, что лекарственное средство не зарегистрировано в Российской Федерации.

真菌感染已构成日益严峻的公共卫生威胁，每年导致数百万例侵袭性感染及大量死亡。现有抗真菌药物种类有限、毒性较高，且耐药性迅速传播，使开发新型治疗策略成为当务之急。本综述系统梳理了面向侵袭性真菌感染的抗真菌药物研发现代趋势。重点关注具有新型作用机制、能够靶向真菌细胞关键结构与代谢通路的药物。文献重点聚焦近十年研究，但同时参考了早期的重要基础性工作。文献搜索在eLibrary.ru、PubMed、Google Scholar和Wally等电子数据库中完成。前沿方向包括：抑制细胞壁主要组分的合成，通过影响细胞膜中麦角固醇、磷脂和鞘脂发挥作用，以及干预胞内关键靶点，如真菌胞内蛋白、信号转导通路、蛋白质生物合成、核酸复制与转录等。讨论抑制真菌细胞壁主要组分生物合成的抑制剂，包括β-1,3-葡聚糖（棘白菌素类、ibrexafungerpY）、β-1,6-葡聚糖、几丁质（nikkomycin ZY）和GPI锚（fosmanogepixY）。分析了作用于麦角固醇（oteseconazoleY、opelconazoleY）、鞘脂（IPC-合酶抑制剂）以及磷脂（mandimycinY）的相关药物。亦涉及真菌激酶、Hsp90、钙调神经磷酸酶、N-肉豆蔻酰转移酶、延伸因子EF-2及核酸抑制剂（olorofimY）。部分药物（olorofimY、fosmanogepixY、 VT-1598、BSG005Y）已进入临床研究阶段。选择性靶点的寻找与联合疗法的开发，被认为是突破耐药性并提升抗真菌疗效的关键方向。

Y Hereafter, it means that the medicinal product is not registered in the Russian Federation.

antifungal agentsantimycoticsinvasive mycosescell wallcell membraneintracellular targetsselective inhibitorsпротивогрибковые препаратыантимикотикиинвазивные микозыклеточная стенкаклеточная мембранавнутриклеточные мишениселективные ингибиторы抗真菌药物抗真菌剂侵袭性真菌感染细胞壁细胞膜胞内靶点选择性抑制剂Правительство Российской ФедерацииGovernment of the Russian FederationGovernment of the Russian FederationMonk BC, Sagatova AA, Hosseini P, et al. Fungal lanosterol 14α-demethylase: a target for next-generation antifungal design. Biochim Biophys Acta Proteins Proteom. 2020;1868(3):140206. doi: 10.1016/j.bbapap.2019.02.008 EDN: IZPYUAFesel PH, Zuccaro A. β-glucan: Crucial component of the fungal cell wall and elusive MAMP in plants. Fungal Genet Biol. 2016;90:53–60. doi: 10.1016/j.fgb.2015.12.004Curto MÁ, Butassi E, Ribas JC, et al. Natural products targeting the synthesis of β(1,3)-D-glucan and chitin of the fungal cell wall. Existing drugs and recent findings. Phytomedicine. 2021;88:153556. doi: 10.1016/j.phymed.2021.153556Emri T, Majoros L, Tóth V, Pócsi I. Echinocandins: production and applications. Appl Microbiol Biotechnol. 2013;97(8):3267–3284. doi: 10.1007/s00253-013-4761-9Sofjan AK, Mitchell A, Shah DN, et al. Rezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapy. J Glob Antimicrob Resist. 2018;14:58–64. doi: 10.1016/j.jgar.2018.02.013Li Y, Lan N, Xu L, Yue Q. Biosynthesis of pneumocandin lipopeptides and perspectives for its production and related echinocandins. Appl Microbiol Biotechnol. 2018;102(23):9881–9891. doi: 10.1007/s00253-018-9382-xJiang K, Luo P, Wang X, Lu L. Insight into advances for the biosynthetic progress of fermented echinocandins of antifungals. Microb Biotechnol. 2024;17(1):e14359. doi: 10.1111/1751-7915.14359Helmy NM, Parang K. Cyclic peptides with antifungal properties derived from bacteria, fungi, plants, and synthetic sources. Pharmaceuticals. 2023;16(6):892. doi: 10.3390/ph16060892Vicente F, Reyes F, Genilloud O. Fungerps: discovery of the glucan synthase inhibitor enfumafungin and development of a new class of antifungal triterpene glycosides. Nat Prod Rep. 2024;41(12):1835–1845. doi: 10.1039/d4np00044gAderiye BI, Oluwole OA. Antifungal agents that target fungal cell wall components: a review. Agri Biol Sci. 2015;1(5):206–216.Onishi J, Meinz M, Thompson J, et al. Discovery of novel antifungal (1,3)-beta-D-glucan synthase inhibitors. Antimicrob Agents Chemother. 2000;44(2):368–377. doi: 10.1128/AAC.44.2.368-377.2000Zhang CW, Zhong XJ, Zhao YuS, et al. Antifungal natural products and their derivatives: a review of their activity and mechanism of actions. Pharmacol. Res.-Mod. Chin. Med. 2023;7:100262. doi: 10.1016/j.prmcm.2023.100262Martins IM, Cortés JC, Muñoz J, et al. Differential activities of three families of specific beta(1,3)glucan synthase inhibitors in wild-type and resistant strains of fission yeast. J Biol Chem. 2011;286(5):3484–3496. doi: 10.1074/jbc.M110.174300Lu Y, Duan MH, Zhao X, et al. Pestiorosins A–F, New Papulacandins isolated from the fungus Pestalotiopsis rosea YNJ21. Chem Biodivers. 2025;22(1):e202401921. doi: 10.1002/cbdv.202401921Roemer T, Delaney S, Bussey H. SKN1 and KRE6 Define a pair of functional homologs encoding putative membrane proteins involved in β-Glucan synthesis. Mol Cell Biol. 1993;13(7):4039–4048. doi: 10.1128/mcb.13.7.4039-4048.1993Kitamura A, Higuchi S, Hata M, et al. Effect of beta-1,6-glucan inhibitors on the invasion process of Candida albicans: potential mechanism of their in vivo efficacy. Antimicrob Agents Chemother. 2009;53(9):3963–3971. doi: 10.1128/AAC.00435-09Roncero C, Sanchez-Diaz A, Valdivieso MH. Chitin synthesis and fungal cell morphogenesis. In: Hoffmeister D, editor. Biochemistry and molecular biology. Vol. III. Cham: Springer International Publishing; 2016. P. 167–190. doi: 10.1007/978-3-319-27790-5_9Larwood DJ. Nikkomycin Z—ready to meet the promise? J. Fungi. 2020;6(4):261. doi: 10.3390/jof6040261Ibe C, Munro CA. Fungal cell wall: An underexploited target for antifungal therapies. PLoS Pathog. 2021;17(4):e1009470. doi: 0.1371/journal.ppat.1009470Shubitz LF, Trinh HT, Perrill RH, et al. Modeling nikkomycin Z dosing and pharmacology in murine pulmonary coccidioidomycosis preparatory to phase 2 clinical trials. J Infect Dis. 2014;209(12):1949–1954. doi: 10.1093/infdis/jiu029Richard ML, Plaine A. Comprehensive analysis of glycosylphosphatidylinositol-anchored proteins in candida albicans. Eukaryot Cell. 2007;6(2):119–133. doi: 10.1128/EC.00297-06Hoenigl M, Sprute R, Egger M, et al. The antifungal pipeline: fosmanogepix, ibrexafungerp, olorofim, opelconazole, and rezafungin. Drugs. 2021;81(15):1703–1729. doi: 10.1007/s40265-021-01611-0Miyazaki M, Horii T, Hata K, et al. In vitro activity of E1210, a novel antifungal, against clinically important yeasts and molds. Antimicrob Agents Chemother. 2011;55(10):4652–4658. doi: 10.1128/AAC.00291-11Watanabe N, Miyazaki M, Horii T, et al. E1210, a new broad-spectrum antifungal, suppresses candida albicans hyphal growth through inhibition of glycosylphosphatidylinositol biosynthesis. Antimicrob Agents Chemother. 2012;56(2):960–971. doi: 10.1128/AAC.00731-11Shaw KJ, Ibrahim AS. Fosmanogepix: A review of the first-in-class broad spectrum agent for the treatment of invasive fungal infections. J. Fungi. 2020;6(4):239. doi: 10.3390/jof6040239Ruiz-Herrera J, Elorza MV, Valentín E, Sentandreu R. Molecular organization of the cell wall of candida albicans and its relation to pathogenicity. FEMS Yeast Res. 2006;6(1):14–29. doi: 10.1111/j.1567-1364.2005.00017.xMiyanishi W, Ojika M, Akase D, et al. D-Mannose Binding, aggregation property, and antifungal activity of amide derivatives of Pradimicin A. Bioorg Med Chem. 2022;55:116590. doi: 10.1016/j.bmc.2021.116590Pan J, Hu C, Yu JH. Lipid biosynthesis as an antifungal target. J Fungi. 2018;4(2):50. doi: 10.3390/jof4020050Campoy S, Adrio JL. Antifungals. Biochem Pharmacol. 2017;133:86–96. doi: 10.1016/j.bcp.2016.11.019Sousa F, Nascimento C, Ferreira D, et al. Reviving the interest in the versatile drug Nystatin: a multitude of strategies to increase its potential as an effective and safe antifungal agent. Adv Drug Deliv Rev. 2023;199:114969. doi: 10.1016/j.addr.2023.114969Kantarcioglu AS, Yucel A, Vidotto V. In vitro activity of a new polyene SPK-843 against Candida spp, Cryptococcus neoformans and Aspergillus spp clinical isolates. J Chemother. 2003;15(3):296–298. doi: 10.1179/joc.2003.15.3.296Kakeya H, Miyazaki Y, Senda H, et al. Efficacy of SPK-843, a novel polyene antifungal, in comparison with Amphotericin B, Liposomal Amphotericin B, and Micafungin against murine pulmonary aspergillosis. Antimicrob Agents Chemother. 2008;52(5):1868–1870. doi: 10.1128/AAC.01369-07Wiederhold NP. The antifungal arsenal: alternative drugs and future targets. Int J Antimicrob Agents. 2018;51(3):333–339. doi: 10.1016/j.ijantimicag.2017.09.002Sobel JD, Donders G, Degenhardt T, et al. Efficacy and safety of Oteseconazole in recurrent vulvovaginal candidiasis. NEJM Evid. 2022;1(8):EVIDoa2100055. doi: 10.1056/EVIDoa2100055Lockhart SR, Fothergill AW, Iqbal N, et al. The investigational fungal Cyp51 inhibitor VT-1129 demonstrates potent in vitro activity against Cryptococcus neoformans and Cryptococcus gattii. Antimicrob Agents Chemother. 2016;60(4):2528–2531. doi: 10.1128/AAC.02770-15Schell WA, Jones AM, Garvey EP, et al. Fungal CYP51 inhibitors VT-1161 and VT-1129 exhibit strong in vitro activity against Candida glabrata and C. krusei isolates clinically resistant to azole and echinocandin antifungal compounds. Antimicrob Agents Chemother. 2017;61(3):e01817–16. doi: 10.1128/AAC.01817-16Wiederhold NP, Patterson HP, Tran BH, et al. Fungal-specific Cyp51 inhibitor VT-1598 demonstrates in vitro activity against candida and Cryptococcus species, endemic fungi, including Coccidioides species, Aspergillus species and Rhizopus Arrhizus. J Antimicrob Chemother. 2018;73(2):404–408. doi: 10.1093/jac/dkx410Neoh CF, Jeong W, Kong DC, Slavin MA. The antifungal pipeline for invasive fungal diseases: what does the future hold? Expert Rev Anti Infect Ther. 2023;21(6):577–594. doi: 10.1080/14787210.2023.2203383Sagatova AA. Strategies to better target fungal squalene monooxygenase. J Fungi. 2021;7(1):49. doi: 10.3390/jof7010049Deng Q, Li Y, He W, et al. A polyene macrolide targeting phospholipids in the fungal cell membrane. Nature. 2025;640(8059):743–751. doi: 10.1038/s41586-025-08678-9Mor V, Rella A, Farnoud AM, et al. Identification of a new class of antifungals targeting the synthesis of fungal sphingolipids. mBio. 2015;6(3):e00647. doi: 10.1128/mBio.00647-15Zhen C, Lu H, Jiang Y. Novel promising antifungal target proteins for conquering invasive fungal infections. Front Microbiol. 2022;13:911322. doi: 10.3389/fmicb.2022.911322Wu X, Gong X, Xie T. Mechanisms of aureobasidin A inhibition and drug resistance in a fungal IPC synthase complex. Nat Commun. 2025;16(1):5010. doi: 10.1038/s41467-025-60423-yMandala SM, Thornton RA, Rosenbach M, et al. Khafrefungin, a novel inhibitor of sphingolipid synthesis. J Biol Chem. 1997;272(51):32709–32714. doi: 10.1074/jbc.272.51.32709Iyer KR, Li SC, Revie NM, et al. Identification of triazenyl indoles as inhibitors of fungal fatty acid biosynthesis with broad-spectrum activity. Cell Chem Biol. 2023;30(7):795–810.e8. doi: 10.1016/j.chembiol.2023.06.005Laakso JA, Raulli R, McElhaney-Feser GE, et al. CT2108A and B: new fatty acid synthase inhibitors as antifungal agents. J Nat Prod. 2003;66(8):1041–1046. doi: 10.1021/np030046gBlankenship JR, Fanning S, Hamaker JJ, Mitchell AP. An extensive circuitry for cell wall regulation in Candida albicans. PLoS Pathog. 2010;6(2):e1000752. doi: 10.1371/journal.ppat.1000752Reinoso-Martín C, Schüller C, Schuetzer-Muehlbauer M, Kuchler K. The yeast protein kinase C cell integrity pathway mediates tolerance to the antifungal drug caspofungin through activation of Slt2p mitogen-activated protein kinase signaling. Eukaryot Cell. 2003;2(6):1200–1210. doi: 10.1128/EC.2.6.1200-1210.2003Jung SI, Rodriguez N, Irrizary J, et al. Yeast casein kinase 2 governs morphology, biofilm formation, cell wall integrity, and host cell damage of Candida albicans. PLoS One. 2017;12(11):e0187721. doi: 10.1371/journal.pone.0187721Puumala E, Nandakumar M, Yiu B, et al. Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans. Nat Commun. 2025;16(1):2156. doi: 10.1038/s41467-025-57346-zRobbins N, Uppuluri P, Nett J, et al. Hsp90 governs dispersion and drug resistance of fungal biofilms. PLoS Pathog. 2011;7(9):e1002257. doi: 10.1371/journal.ppat.1002257Yuan R, Tu J, Sheng C, et al. Effects of Hsp90 inhibitor ganetespib on inhibition of azole-resistant Candida albicans. Front Microbiol. 2021;12:680382. doi: 10.3389/fmicb.2021.680382Tu B, Yin G, Li H. Synergistic effects of vorinostat (SAHA) and azoles against Aspergillus species and their biofilms. BMC Microbiol. 2020;20(1):28. doi: 10.1186/s12866-020-1718-xZheng YQ, Pan KS, Latgé JP, et al Calcineurin A is essential in the regulation of asexual development, stress responses and pathogenesis in Talaromyces marneffei. Front Microbiol. 2020;10:3094. doi: 10.3389/fmicb.2019.03094Steinbach WJ, Cramer RA Jr, Perfect BZ, et al. Calcineurin controls growth, morphology, and pathogenicity in Aspergillus fumigatus. Eukaryot Cell. 2006;5(7):1091–1103. doi: 10.1128/EC.00139-06Rivera A, Young Lim W, Park E, et al. Enhanced fungal specificity and in vivo therapeutic efficacy of a C-22-modified FK520 analog against C. neoformans. mBio. 2023;14(5):e0181023. doi: 10.1128/mbio.01810-23Ballou LM, Lin RZ. Rapamycin and mTOR kinase inhibitors. J Chem Biol. 2008;1(1-4):27–36. doi: 10.1007/s12154-008-0003-5Utsumi T, Matsuzaki K, Kiwado A, et al. Identification and characterization of protein Nmyristoylation occurring on four human mitochondrial proteins, SAMM50, TOMM40, MIC19, and MIC25. PLoS ONE. 2018;13(11):e0206355. doi: 10.1371/journal.pone.0206355Javid S, Ather H, Hani U, et al. Discovery of novel myristic acid derivatives as n-myristoyltransferase inhibitors: design, synthesis, analysis, computational studies and antifungal activity. Antibiotics. 2023;12(7):1167. doi: 10.3390/antibiotics12071167Yeates C. Icofungipen (PLIVA). Curr Opin Investig Drugs. 2005;6(8):838–844.Shao Y, Molestak E, Su W, et al. Sordarin — an anti-fungal antibiotic with a unique modus operandi. Br J Pharmacol. 2022;179(6):1125–1145. doi: 10.1111/bph.15724Parish CA, Smith SK, Calati K, et al. Isolation and structure elucidation of parnafungins, antifungal natural products that inhibit mRNA polyadenylation. J Am Chem Soc. 2008;130(22):7060–7066. doi: 10.1021/ja711209pQiao J, Gao P, Jiang X, Fang H. In vitro antifungal activity of farnesyltransferase inhibitors against clinical isolates of Aspergillus and Candida. Ann Clin Microbiol Antimicrob. 2013;12:37. doi: 10.1186/1476-0711-12-37du Pre S., Birch M., Law D., et al. The dynamic influence of Olorofim (F901318) on the cell morphology and organization of living cells of Aspergillus fumigatus. J Fungi. 2020;6:47. doi: 10.3390/jof6020047Wiederhold NP. Pharmacodynamics, mechanisms of action and resistance, and spectrum of activity of new antifungal agents. J Fungi. 2022;8(8):857. doi: 10.3390/jof8080857Odds FC. Genomics, molecular targets and the discovery of antifungal drugs. Rev Iberoam Micol. 2005;22(4):229–237. doi: 10.1016/s1130-1406(05)70048-6Gabriel I. 'Acridines' as new horizons in antifungal treatment. Molecules. 2020;25(7):1480. doi: 3390/molecules25071480