Cell Wall-Modifying Antifungal Drugs

Perlin, David S.

doi:10.1007/82_2019_188

Cited by 12 publications

(16 citation statements)

References 94 publications

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“…Another explanation for the weak fungistatic effect of echinocandins is that decreased amount of β-glucan induces a variety of stress adaptation pathways resulting in increased cell wall chitin [ 10 , 24 , 25 , 26 ]. Increased chitin content helps to stabilize the fungal cell wall, therefore mitigating the impact of echinocandins.…”

Section: Discussionmentioning

confidence: 99%

“…Increased chitin content helps to stabilize the fungal cell wall, therefore mitigating the impact of echinocandins. Although this adaptive response does not lead to mutations in the FKS genes, the early adaptation to echinocandin exposure enhances survival of the drug effect and may allow the development of stable resistance mechanisms over time for surviving cells, possibly leading to clinical resistance in the long run [ 24 , 25 , 26 ]. The mini-paradoxical effect in RPMI-1640, which disappeared in the case of some isolates in the presence of serum, may represent such adaptation.…”

Section: Discussionmentioning

confidence: 99%

“…The high protein binding decreases the free (i.e., active) echinocandin concentration as modeled by the presence of 50% serum, which is mirrored in elevated MICs [ 10 ]. Lower free drug levels induce less compensatory chitin synthesis; thus, higher k values at higher concentrations with serum may be explained by the enhancement of the killing activities of echinocandins due to lower cell wall chitin, compared to RPMI-1640 ( Figure 2 ) [ 10 , 26 ]. Although chitin content was not measured in our study, other authors found elevated chitin content in C. auris , compared to other species more susceptible to echinocandins [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

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Comparison of In Vitro Killing Activity of Rezafungin, Anidulafungin, Caspofungin, and Micafungin against Four Candida auris Clades in RPMI-1640 in the Absence and Presence of Human Serum

et al. 2021

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Candida auris is an emerging and frequently multidrug-resistant pathogen against which the echinocandins are the preferred therapeutic option. We compared killing activities of anidulafungin, caspofungin, micafungin, and rezafungin against 13 isolates representing four C. auris clades (South Asian n = 3; East Asian n = 3; South African n = 3; South American n = 4, of which two were of environmental origin). Minimum inhibitory concentration MICs and killing kinetics in RPMI-1640 and RPMI-1640 plus 50% serum (50% serum) were determined. The four echinocandins were never fungicidal and induced large aggregates in RPMI-1640 and, less markedly, in 50% serum. Colony forming unit CFU decreases were found more consistently in 50% serum than in RPMI-1640. Isolates from the East Asian clade were killed at ≥1–≥ 4 mg/L with all echinocandins regardless of media. Anidulafungin and micafungin produced killing at peak drug serum concentration (8 mg/L) against environmental but not clinical isolates from the South American and the South African clades. Micafungin at ≥8 mg/L but not anidulafungin produced CFU decreases against the South Asian clade as well. In 50% serum, rezafungin at ≥1–≥ 8 mg/L produced killing against all four clades. The next generation echinocandin, rezafungin, showed the same or better activity at clinically attainable trough concentration regardless of media, compared with anidulafungin, caspofungin, and micafungin against all four tested C. auris clades.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Comparison of In Vitro Killing Activity of Rezafungin, Anidulafungin, Caspofungin, and Micafungin against Four Candida auris Clades in RPMI-1640 in the Absence and Presence of Human Serum

et al. 2021

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“…resistant to multiple azoles, and 8 μg/mL of micafungin demonstrated a 57 % antifungal rate in C. parapsilosis (Gil-Alonso et al 2015 ). Nevertheless, probably due to the differences in cell wall composition or structure, this class is largely inactive in most filamentous fungi including Zygomycetes and Fusarium species (Perlin 2020 ). In addition, C. neoformans is naturally resistant to echinocandins, which are completely ineffective in treating cryptococcosis (Denning 2003 ).…”

Section: Current Antifungal Drugs Used In Clinicsmentioning

confidence: 99%

Drug repurposing strategies in the development of potential antifungal agents

Zhang

Liu

Zeng

et al. 2021

Appl Microbiol Biotechnol

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The morbidity and mortality caused by invasive fungal infections are increasing across the globe due to developments in transplant surgery, the use of immunosuppressive agents, and the emergence of drug-resistant fungal strains, which has led to a challenge in terms of treatment due to the limitations of three classes of drugs. Hence, it is imperative to establish effective strategies to identify and design new antifungal drugs. Drug repurposing is a potential way of expanding the application of existing drugs. Recently, various existing drugs have been shown to be useful in the prevention and treatment of invasive fungi. In this review, we summarize the currently used antifungal agents. In addition, the most up-to-date information on the effectiveness of existing drugs with antifungal activity is discussed. Moreover, the antifungal mechanisms of existing drugs are highlighted. These data will provide valuable knowledge to stimulate further investigation and clinical application in this field. Key points • Conventional antifungal agents have limitations due to the occurrence of drug-resistant strains. • Non-antifungal drugs act as antifungal agents in various ways toward different targets. • Non-antifungal drugs with antifungal activity are demonstrated as effective antifungal strategies.

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“…Intravenous caspofungin is now used routinely in the treatment of systemic fungal infection as first-line choice of drug for the treatment of Candida species ( Patil and Majumdar, 2017 ; Perlin, 2020 ). Caspofungin non-competitively inhibits Fks1, the catalytic subunit of β-1,3 glucan synthase, preventing the de novo formation of β-1,3 glucan, thereby compromising the assembly of the cantilevered glucan-chitin wall exoskeleton ( Hoang, 2001 ; Steinbach and Perfect, 2003 ; Denning, 2003 ; Odds et al, 2003 ; Walker et al, 2010 ; Földi et al, 2012 ; Lenardon et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between the calcineurin and cell wall integrity pathways prevents chitin overexpression in Candida albicans

Dantas

Nogueira

Lee

et al. 2021

Journal of Cell Science

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Echinocandins such as caspofungin are front line antifungal drugs that compromise β-1,3 glucan synthesis in the cell wall. Recent reports have shown that fungal cells can resist killing by caspofungin by up-regulation of chitin synthesis, thereby sustaining cell wall integrity. When echinocandins are removed, the chitin content of cells quickly returns to basal levels, suggesting that there is a fitness cost associated with having elevated levels of chitin in the cell wall. We show here that simultaneous activation of the calcineurin and CWI pathways generates a sub-population of Candida albicans yeast cells that have supra-normal chitin levels interspersed throughout the inner and outer cell wall, and that these cells are non-viable, perhaps due to loss of wall elasticity required for cell expansion and growth. Mutations in the Ca2+-calcineurin pathway prevented the formation of these non-viable super high chitin cells by negatively regulating chitin synthesis driven by the CWI pathway. The Ca2+-calcineurin pathway may therefore act as an attenuator that prevents the overproduction of chitin by coordinating both chitin upregulation and negative regulation of the CWI signaling pathway.

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Cell Wall-Modifying Antifungal Drugs

Cited by 12 publications

References 94 publications

Comparison of In Vitro Killing Activity of Rezafungin, Anidulafungin, Caspofungin, and Micafungin against Four Candida auris Clades in RPMI-1640 in the Absence and Presence of Human Serum

Comparison of In Vitro Killing Activity of Rezafungin, Anidulafungin, Caspofungin, and Micafungin against Four Candida auris Clades in RPMI-1640 in the Absence and Presence of Human Serum

Drug repurposing strategies in the development of potential antifungal agents

Crosstalk between the calcineurin and cell wall integrity pathways prevents chitin overexpression in Candida albicans

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