AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home International Journal of Oral Science Article
PDF (5.3 MB)
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Original Article | Open Access

Artemisinins inhibit oral candidiasis caused by Candida albicans through the repression on its hyphal development

Xiaoyue Liang1,, Ding Chen1,, Jiannan Wang1, Binyou Liao1, Jiawei Shen1, Xingchen Ye1, Zheng Wang1, Chengguang Zhu1, Lichen Gou1, Xinxuan Zhou1, Lei Cheng1,2, Biao Ren1 ( ), Xuedong Zhou1,2( )
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China

These authors contributed equally: Xiaoyue Liang, Ding Chen

Show Author Information

Abstract

Candida albicans is the most abundant fungal species in oral cavity. As a smart opportunistic pathogen, it increases the virulence by switching its forms from yeasts to hyphae and becomes the major pathogenic agent for oral candidiasis. However, the overuse of current clinical antifungals and lack of new types of drugs highlight the challenges in the antifungal treatments because of the drug resistance and side effects. Anti-virulence strategy is proved as a practical way to develop new types of anti-infective drugs. Here, seven artemisinins, including artemisinin, dihydroartemisinin, artemisinic acid, dihydroartemisinic acid, artesunate, artemether and arteether, were employed to target at the hyphal development, the most important virulence factor of C. albicans. Artemisinins failed to affect the growth, but significantly inhibited the hyphal development of C. albicans, including the clinical azole resistant isolates, and reduced their damage to oral epithelial cells, while arteether showed the strongest activities. The transcriptome suggested that arteether could affect the energy metabolism of C. albicans. Seven artemisinins were then proved to significantly inhibit the productions of ATP and cAMP, while reduced the hyphal inhibition on RAS1 overexpression strain indicating that artemisinins regulated the Ras1-cAMP-Efg1 pathway to inhibit the hyphal development. Importantly, arteether significantly inhibited the fungal burden and infections with no systemic toxicity in the murine oropharyngeal candidiasis models in vivo caused by both fluconazole sensitive and resistant strains. Our results for the first time indicated that artemisinins can be potential antifungal compounds against C. albicans infections by targeting at its hyphal development.

References

1

Belvoncikova, P., Splichalova, P., Videnska, P. & Gardlik, R. The human mycobiome: colonization, composition and the role in health and disease. J. Fungi 8, 1046 (2022).
Crossref Google Scholar
2

Ghannoum, M. A. et al. Characterization of the oral fungal microbiome (mycobiome) in healthy individuals. PLoS Pathog. 6, e1000713 (2010).
Crossref Google Scholar
3

Lopes, J. P. & Lionakis, M. S. Pathogenesis and virulence of Candida albicans. Virulence 13, 89–121 (2022).
Crossref Google Scholar
4

Proctor, D. M., Drummond, R. A., Lionakis, M. S. & Segre, J. A. One population, multiple lifestyles: commensalism and pathogenesis in the human mycobiome. Cell Host Microbe 31, 539–553 (2023).
Crossref Google Scholar
5

Miceli, M. H., Díaz, J. A. & Lee, S. A. Emerging opportunistic yeast infections. Lancet Infect. Dis. 11, 142–151 (2011).
Crossref Google Scholar
6

Mahalingam, S. S., Jayaraman, S. & Pandiyan, P. Fungal colonization and infections—interactions with other human diseases. Pathogens 11, 212 (2022).
Crossref Google Scholar
7

Saftien, A., Puschhof, J. & Elinav, E. Fungi and cancer. Gut 72, 1410–1425 (2023).
Crossref Google Scholar
8

Talapko, J. et al. Candida albicans—the virulence factors and clinical manifestations of infection. J. Fungi 7, 79 (2021).
Crossref Google Scholar
9

Swidergall, M. & Filler, S. G. Oropharyngeal candidiasis: fungal invasion and epithelial cell responses. PLoS Pathog. 13, e1006056 (2017).
Crossref Google Scholar
10

Patel, M. Oral cavity and Candida albicans: colonisation to the development of infection. Pathogens 11, 335 (2022).
Crossref Google Scholar
11

Zhou, Y., Cheng, L., Lei, Y. L., Ren, B. & Zhou, X. The interactions between candida albicans and mucosal immunity. Front. Microbiol. 12, 652765 (2021).
Crossref Google Scholar
12

Sultan, A. S., Theofilou, V. I., Alfaifi, A., Montelongo-Jauregui, D. & Jabra-Rizk, M.-A. Is Candida albicans an opportunistic oncogenic pathogen? PLoS Pathog. 18, e1010413 (2022).
Crossref Google Scholar
13

Dohlman, A. B. et al. A pan-cancer mycobiome analysis reveals fungal involvement in gastrointestinal and lung tumors. Cell 185, 3807–3822.e3812 (2022).
Crossref Google Scholar
14

Chen, H., Zhou, X., Ren, B. & Cheng, L. The regulation of hyphae growth in Candida albicans. Virulence 11, 337–348 (2020).
Crossref Google Scholar
15

Sundstrom, P. Adhesins in Candida albicans. Curr. Opin. Microbiol. 2, 353–357 (1999).
Crossref Google Scholar
16

Naglik, J. R., König, A., Hube, B. & Gaffen, S. L. Candida albicans–epithelial interactions and induction of mucosal innate immunity. Curr. Opin. Microbiol. 40, 104–112 (2017).
Crossref Google Scholar
17

Lachat, J. et al. Trans-cellular tunnels induced by the fungal pathogen Candida albicans facilitate invasion through successive epithelial cells without host damage. Nat. Commun. 13, 3781 (2022).
Crossref Google Scholar
18

Zhou, Y. et al. ERG3 and ERG11 genes are critical for the pathogenesis of Candida albicansduring the oral mucosal infection. Int. J. Oral. Sci. 10, 9 (2018).
Crossref Google Scholar
19

Moyes, D. L. et al. Candidalysin is a fungal peptide toxin critical for mucosal infection. Nature 532, 64–68 (2016).
Crossref Google Scholar
20

Kasper, L. et al. The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes. Nat. Commun. 9, 4260 (2018).
Crossref Google Scholar
21

Austermeier, S., Kasper, L., Westman, J. & Gresnigt, M. S. I want to break free – macrophage strategies to recognize and kill Candida albicans, and fungal counter-strategies to escape. Curr. Opin. Microbiol. 58, 15–23 (2020).
Crossref Google Scholar
22

König, A., Hube, B. & Kasper, L. The dual function of the fungal toxin candidalysin during candida albicans—macrophage interaction and virulence. Toxins 12, 469 (2020).
Crossref Google Scholar
23

Köhler, J. R. & Fink, G. R. Candida albicans strains heterozygous and homozygous for mutations in mitogen-activated protein kinase signaling components have defects in hyphal development. Proc. Natl. Acad. Sci. 93, 13223–13228 (1996).
Crossref Google Scholar
24

Davis, D. Adaptation to environmental pH in Candida albicans and its relation to pathogenesis. Curr. Genet. 44, 1–7 (2003).
Crossref Google Scholar
25

Román, E., Correia, I., Prieto, D., Alonso, R. & Pla, J. The HOG MAPK pathway in Candida albicans: more than an osmosensing pathway. Int. Microbiol. 23, 23–29 (2020).
Crossref Google Scholar
26

Liao, B. et al. The two-component signal transduction system and its regulation in Candida albicans. Virulence 12, 1884–1899 (2021).
Crossref Google Scholar
27

Liu, H. Transcriptional control of dimorphism in Candida albicans. Curr. Opin. Microbiol. 4, 728–735 (2001).
Crossref Google Scholar
28

Davis‐Hanna, A., Piispanen, A. E., Stateva, L. I. & Hogan, D. A. Farnesol and dodecanol effects on the Candida albicans Ras1‐cAMP signalling pathway and the regulation of morphogenesis. Mol. Microbiol. 67, 47–62 (2008).
Crossref Google Scholar
29

Silao, F. G. S. et al. Mitochondrial proline catabolism activates Ras1/cAMP/PKA-induced filamentation in Candida albicans. PLOS Genet. 15, e1007976 (2019).
Crossref Google Scholar
30

Fang, H. M. & Wang, Y. RA domain‐mediated interaction of Cdc35 with Ras1 is essential for increasing cellular cAMP level for Candida albicans hyphal development. Mol. Microbiol. 61, 484–496 (2006).
Crossref Google Scholar
31

Feng, Q., Summers, E., Guo, B. & Fink, G. Ras signaling is required for serum-induced hyphal differentiation in Candida albicans. J. Bacteriol. 181, 6339–6346 (1999).
Crossref Google Scholar
32

Huang, G., Huang, Q., Wei, Y., Wang, Y. & Du, H. Multiple roles and diverse regulation of the Ras/cAMP/protein kinase a pathway in Candida albicans. Mol. Microbiol. 111, 6–16 (2019).
Crossref Google Scholar
33

Xu, X.-L. et al. Bacterial peptidoglycan triggers Candida albicans hyphal growth by directly activating the adenylyl cyclase Cyr1p. Cell Host Microbe 4, 28–39 (2008).
Crossref Google Scholar
34

Lin, C.-J., Wu, C.-Y., Yu, S.-J. & Chen, Y.-L. Protein kinase a governs growth and virulence in Candida tropicalis. Virulence 9, 331–347 (2018).
Crossref Google Scholar
35

Cloutier, M. et al. The two isoforms of the cAMP-dependent protein kinase catalytic subunit are involved in the control of dimorphism in the human fungal pathogen Candida albicans. Fungal Genet. Biol. 38, 133–141 (2003).
Crossref Google Scholar
36

Huang, M. Y., Woolford, C. A., May, G., McManus, C. J. & Mitchell, A. P. Circuit diversification in a biofilm regulatory network. PLoS Pathog. 15, e1007787 (2019).
Crossref Google Scholar
37

Zeidler, U. et al. UME6 is a crucial downstream target of other transcriptional regulators of true hyphal development in Candida albicans. FEMS Yeast Res. 9, 126–142 (2009).
Crossref Google Scholar
38

Cravener, M. V. et al. Reinforcement amid genetic diversity in the Candida albicans biofilm regulatory network. PLoS Pathog. 19, e1011109 (2023).
Crossref Google Scholar
39

Singh, A., Sharma, S. & Khuller, G. K. cAMP regulates vegetative growth and cell cycle in Candida albicans. Mol. Cell. Biochem. 304, 331–341 (2007).
Crossref Google Scholar
40

Bai, C. et al. Characterization of a hyperactive Cyr1 mutant reveals new regulatory mechanisms for cellular cAMP levels in Candida albicans. Mol. Microbiol. 82, 879–893 (2011).
Crossref Google Scholar
41

Bu, Q.-R., Bao, M.-Y., Yang, Y., Wang, T.-M. & Wang, C.-Z. Targeting virulence factors of Candida albicans with natural products. Foods 11, 2951 (2022).
Crossref Google Scholar
42

Cui, J., Ren, B., Tong, Y., Dai, H. & Zhang, L. Synergistic combinations of antifungals and anti-virulence agents to fight against Candida albicans. Virulence 6, 362–371 (2015).
Crossref Google Scholar
43

Ivanov, M., Ćirić, A. & Stojković, D. Emerging Antifungal Targets and Strategies. Int. J. Mol. Sci. 23, 2756 (2022).
Crossref Google Scholar
44

Lee, Y., Puumala, E., Robbins, N. & Cowen, L. E. Antifungal drug resistance: molecular mechanisms in Candida albicans and beyond. Chem. Rev. 121, 3390–3411 (2020).
Crossref Google Scholar
45

Revie, N. M., Iyer, K. R., Robbins, N. & Cowen, L. E. Antifungal drug resistance: evolution, mechanisms and impact. Curr. Opin. Microbiol. 45, 70–76 (2018).
Crossref Google Scholar
46

Gray, K. C. et al. Amphotericin primarily kills yeast by simply binding ergosterol. Proc. Natl. Acad. Sci. 109, 2234–2239 (2012).
Crossref Google Scholar
47

Sawistowska-Schröder, E., Kerridge, D. & Perry, H. Echinocandin inhibition of 1, 3‐β‐D‐glucan synthase from Candida albicans. FEBS Lett. 173, 134–138 (1984).
Crossref Google Scholar
48

Hüttel, W. Echinocandins: structural diversity, biosynthesis, and development of antimycotics. Appl. Microbiol. Biotechnol. 105, 55–66 (2021).
Crossref Google Scholar
49

Fisher, M. C. & Denning, D. W. The WHO fungal priority pathogens list as a game-changer. Nat. Rev. Microbiol. https://doi.org/10.1038/s41579-023-00861-x (2023).
Crossref Google Scholar
50

Fisher, M. C. et al. Tackling the emerging threat of antifungal resistance to human health. Nat. Rev. Microbiol. 20, 557–571 (2022).
Crossref Google Scholar
51

Perlin, D. S., Rautemaa-Richardson, R. & Alastruey-Izquierdo, A. The global problem of antifungal resistance: prevalence, mechanisms, and management. Lancet Infect. Dis. 17, e383–e392 (2017).
Crossref Google Scholar
52

Azie, N., Angulo, D., Dehn, B. & Sobel, J. D. Oral Ibrexafungerp: an investigational agent for the treatment of vulvovaginal candidiasis. Expert Opin. Investig. Drugs 29, 893–900 (2020).
Crossref Google Scholar
53

Hoenigl, M. et al. The antifungal pipeline: fosmanogepix, ibrexafungerp, olorofim, opelconazole, and rezafungin. Drugs 81, 1703–1729 (2021).
Crossref Google Scholar
54

Fernandes, C. M. et al. The Future of antifungal drug therapy: novel compounds and targets. Antimicrob. Agents Chemother. 65, e01719–e01720 (2021).
Crossref Google Scholar
55

Cegelski, L., Marshall, G. R., Eldridge, G. R. & Hultgren, S. J. The biology and future prospects of antivirulence therapies. Nat. Rev. Microbiol. 6, 17–27 (2008).
Crossref Google Scholar
56

Dickey, S. W., Cheung, G. Y. C. & Otto, M. Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nat. Rev. Drug Discov. 16, 457–471 (2017).
Crossref Google Scholar
57

Fleitas Martínez, O., Cardoso, M. H., Ribeiro, S. M. & Franco, O. L. Recent advances in anti-virulence therapeutic strategies with a focus on dismantling bacterial membrane microdomains, toxin neutralization, quorum-sensing interference and biofilm inhibition. Front. Cell. Infect. Microbiol. 9, 74 (2019).
Crossref Google Scholar
58

Cao, Z. & Cock, I. E. Potential of traditional chinese medicines to treat drug-resistant bacterial infections: a review. Pharmacogn. Commun. 11, 186–194 (2021).
Crossref Google Scholar
59

Chi, Y. et al. Natural products from traditional medicine as promising agents targeting at different stages of oral biofilm development. Front. Microbiol. 13, 955459 (2022).
Crossref Google Scholar
60

Zhu, C. et al. Artemisinin elevates the ergosterol levels of Candida albicans to synergize with amphotericin B against oral candidiasis. Int. J. Antimicrob. Agents 58, 106394 (2021).
Crossref Google Scholar
61

Brown, G. D. et al. Hidden killers: human fungal infections. Sci. Transl. Med. 4, 165rv113 (2012).
Crossref Google Scholar
62

Eyre, D. W. et al. A Candida auris outbreak and its control in an intensive care setting. N. Engl. J. Med. 379, 1322–1331 (2018).
Crossref Google Scholar
63

Du, H. et al. Candida auris: Epidemiology, biology, antifungal resistance, and virulence. PLoS Pathog. 16, e1008921 (2020).
Crossref Google Scholar
64

Du, H. et al. Candida vulturna outbreak caused by cluster of multidrug-resistant strains, China. Emerg. Infect. Dis. 29, 1425 (2023).
Crossref Google Scholar
65

Pu, Z. et al. Assessment of the anti-virulence potential of extracts from four plants used in traditional Chinese medicine against multidrug-resistant pathogens. BMC Complement. Med. Ther. 20, 1–10 (2020).
Crossref Google Scholar
66

Zeng, L., Lin, F. & Ling, B. Effect of traditional Chinese medicine monomers interfering with quorum-sensing on virulence factors of extensively drug-resistant Acinetobacter baumannii. Front. Pharmacol. 14, 1135180 (2023).
Crossref Google Scholar
67

Wang, H. et al. Chlorogenic acid attenuates virulence factors and pathogenicity of pseudomonas aeruginosa by regulating quorum sensing. Appl. Microbiol. Biotechnol. 103, 903–915 (2019).
Crossref Google Scholar
68

Salam, A. M. & Quave, C. L. Opportunities for plant natural products in infection control. Curr. Opin. Microbiol. 45, 189–194 (2018).
Crossref Google Scholar
69

Chung, I.-Y. et al. Artemisinin displays bactericidal activity via copper-mediated DNA damage. Virulence 13, 149–159 (2022).
Crossref Google Scholar
70

Haynes, R. K. & Krishna, S. Artemisinins: activities and actions. Microbes Infect. 6, 1339–1346 (2004).
Crossref Google Scholar
71

Hartwig, C. L. et al. Accumulation of artemisinin trioxane derivatives within neutral lipids of plasmodium falciparum malaria parasites is endoperoxide-dependent. Biochem. Pharmacol. 77, 322–336 (2009).
Crossref Google Scholar
72

Eckstein-Ludwig, U. et al. Artemisinins target the SERCA of Plasmodium falciparum. Nature 424, 957–961 (2003).
Crossref Google Scholar
73

Zhang, K. et al. Streptococcus mutans sigX-inducing Peptide Inhibits Candida albicans Virulence and Oral Candidiasis through the Ras1-cAMP-Efg1 Pathway. Int. J. Antimicrob. Agents, 106855, https://doi.org/10.1016/j.ijantimicag.2023.106855 (2023).
Crossref Google Scholar
74

Zhou, Y. et al. Lovastatin synergizes with itraconazole against planktonic cells and biofilms of Candida albicans through the regulation on ergosterol biosynthesis pathway. Appl. Microbiol. Biotechnol. 102, 5255–5264 (2018).
Crossref Google Scholar
75

Zhou, Y. et al. Candida albicans CHK1 gene from two-component system is essential for its pathogenicity in oral candidiasis. Appl. Microbiol. Biotechnol. 105, 2485–2496 (2021).
Crossref Google Scholar
76

Wei, Y. et al. Extracellular vesicles of Candida albicans regulate its own growth through the l-arginine/nitric oxide pathway. Appl. Microbiol. Biotechnol. 107, 355–367 (2023).
Crossref Google Scholar
77

Chen, H. et al. Dimethylaminododecyl methacrylate inhibits Candida albicans and oropharyngeal candidiasis in a pH-dependent manner. Appl. Microbiol. Biotechnol. 104, 3585–3595 (2020).
Crossref Google Scholar
International Journal of Oral Science
Volume 15,
2023
Article number: 40
DOI: 10.1038/s41368-023-00245-0
Cite this article:
Liang X, Chen D, Wang J, et al. Artemisinins inhibit oral candidiasis caused by Candida albicans through the repression on its hyphal development. International Journal of Oral Science, 2023, 15: 40. https://doi.org/10.1038/s41368-023-00245-0

160

Views

1

Downloads

8

Crossref

7

Web of Science

8

Scopus

Altmetrics
Received: 09 August 2023
Revised: 28 August 2023
Accepted: 28 August 2023
Published: 12 September 2023
© The Author(s) 2023

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Return