Delicate metabolic control and coordinated stress response critically determine antifungal tolerance of Candida albicans biofilm persisters
Open accessAbstract
Candida infection has emerged as a critical health care burden worldwide, owing to the formation of robust biofilms against common antifungals. Recent evidence shows that multidrug-tolerant persisters critically account for biofilm recalcitrance, but their underlying biological mechanisms are poorly understood. Here, we first investigated the phenotypic characteristics of Candida biofilm persisters under consecutive harsh treatments of amphotericin B. The prolonged treatments effectively killed the majority of the cells of biofilms derived from representative strains of Candida albicans , Candida glabrata , and Candida tropicalis but failed to eradicate a small fraction of persisters. Next, we explored the tolerance mechanisms of the persisters through an investigation of the proteomic profiles of C. albicans biofilm persister fractions by liquid chromatography-tandem mass spectrometry. The C. albicans biofilm persisters displayed a specific proteomic signature, with an array of 205 differentially expressed proteins. The crucial enzymes involved in glycolysis, the tricarboxylic acid cycle, and protein synthesis were markedly downregulated, indicating that major metabolic activities are subdued in the persisters. It is noteworthy that certain metabolic pathways, such as the glyoxylate cycle, were able to be activated with significantly increased levels of isocitrate lyase and malate synthase. Moreover, a number of important proteins responsible for Candida growth, virulence, and the stress response were greatly upregulated. Interestingly, the persisters were tolerant to oxidative stress, despite highly induced intracellular superoxide. The current findings suggest that delicate metabolic control and a coordinated stress response may play a crucial role in mediating the survival and antifungal tolerance of Candida biofilm persisters.
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Dormant cells have been observed in various cases of antifungal persistence, such as AmB-tolerant C. albicans biofilms and a mouse model of pulmonary cryptococcosis.
“Dormant cells have been observed in various cases of antifungal persistence, such as in AmB-tolerant C. albicans biofilms and in a mouse model of pulmonary cryptococcosis [3,33].”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [33]
Antifungal persistence is mainly identified in Candida-associated biofilms.
“Currently, antifungal persistence is mainly identified in Candida-associated biofilms [2,32,33].”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [33]
Pgk1 and Hxk2 involved in glycolysis, together with Idh2 and Mdh1 involved in the TCA cycle, are down-regulated in AmB-tolerant C. albicans biofilm persisters.
“Specifically, phosphoglycerate kinase (Pgk1) and hexokinase-2 (Hxk2) involved in glycolysis, together with isocitrate dehydrogenase (Idh2) and malate dehydrogenase (Mdh1) involved in TCA cycle are down-regulated [33].”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [33]
Major energy-generating pathways, including glycolysis, the TCA cycle and the pentose phosphate pathway, are down-regulated in AmB-tolerant C. albicans biofilm persisters.
“Through proteomics, Li and colleagues found that the major energy-generating pathways were down-regulated in AmB-tolerant C. albicans biofilm persisters, including glycolysis, tricarboxylic acid (TCA) cycle and pentose phosphate pathway (PPP).”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [33]
In AmB-tolerant C. albicans biofilm persisters, TMA19, EF-1, EF-2, EF-Tu, Mcr1, Erg10 and Erg13 are all down-regulated.
“In AmB-tolerant C. albicans biofilm persisters, conserved protein TMA19 involved in protein synthesis and cell growth, elongation factors EF-1, EF-2, EF-Tu involved in translational elongation, Mcr1, Erg10, Erg13 involved in ergosterol biosynthesis are all down-regulated [33].”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [33]
Key enzymes in the glyoxylate cycle, Icl1 and Mls1, together with the rate-limiting enzyme in gluconeogenesis, Fbp1, are significantly up-regulated in C. albicans biofilm persisters.
“Conversely, key enzymes in glyoxylate cycle, named isocitrate lyase (Icl1) and malate synthase (Mls1), together with rate-limiting enzyme in gluconeogenesis named fructose-1,6-bisphosphatase (Fbp1) are significantly up-regulated in C. albicans biofilm persisters [33].”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [33]
Other proteins from the heat shock protein (HSP) family, including Hsp90, Hsp21, Hsp104, HSP Ssc1, and Hsp70 molecular chaperone protein Kar2, are highly expressed in AmB-tolerant persisters.
“In addition to Hsp12, other proteins from the heat shock protein (HSP) family, including Hsp90, Hsp21, Hsp104, HSP Ssc1, and Hsp70 molecular chaperone protein Kar2, are highly expressed in AmB-tolerant persisters [33].”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [33]
Antifungal persistence is most commonly observed in biofilm rather than in planktonic cells.
“Antifungal persistence is most commonly observed in biofilm rather than in planktonic cells [2,33,34]”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [33]
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- Authors
- Li, P., Seneviratne, C. J., Alpi, E., Vizcaino, J. A., & Jin, L.
- Affiliations
- University of Hong Kong (HK)
- National University of Singapore (SG)
- European Bioinformatics Institute (GB)
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2015-10
- Volume
- 59
- Issue
- 10
- Pages
- 6101-6112
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC4576078
- OpenAlex
- W988015238
- Cited by
- 95
- References
- 60
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 7 · 2023: 10 · 2022: 9 · 2021: 8 · 2020: 9 · 2019: 6 · 2018: 9 · 2017: 15 · 2016: 4 · 2015: 1
- FWCI
- 7.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- Wellcome Trust (WT101477MA)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
- Keywords
- Candida albicans, antifungal tolerance, amphotericin B, Candida glabrata, Candida tropicalis, proteomic signatures, glyoxylate cycle, isocitrate lyase, malate synthase, oxidative stress, superoxide, stress response, multidrug tolerance
- MeSH terms
- Amphotericin B, Antifungal Agents, Candida albicans, Biofilms
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