The antifungal pipeline: a reality check

Perfect, John R.

doi:10.1038/nrd.2017.46

Cited by 866Antifungal resistance and susceptibilityFungal Plant Pathogen ControlFungal Infections and Studies

The antifungal pipeline: a reality check

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Perfect, John R.·2017·Nature Reviews Drug Discovery

DOI 10.1038/nrd.2017.46PMC PMC5760994

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Abstract

Invasive fungal infections continue to appear in record numbers as the immunocompromised population of the world increases, owing partially to the increased number of individuals who are infected with HIV and partially to the successful treatment of serious underlying diseases. The effectiveness of current antifungal therapies - polyenes, flucytosine, azoles and echinocandins (as monotherapies or in combinations for prophylaxis, or as empiric, pre-emptive or specific therapies) - in the management of these infections has plateaued. Although these drugs are clinically useful, they have several limitations, such as off-target toxicity, and drug-resistant fungi are now emerging. New antifungals are therefore needed. In this Review, I discuss the robust and dynamic antifungal pipeline, including results from preclinical academic efforts through to pharmaceutical industry products, and describe the targets, strategies, compounds and potential outcomes.

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The inhibitor MGCD290 targets histone deacetylase Hos2 and is currently in Phase II clinical trials.
“The inhibitor MGCD290 is a new type of antifungal drug targeting the histone deacetylase Hos2 and currently in Phase II clinical trials35”
From Targeting epigenetic regulators to overcome drug resistance in the emerging human fungal pathogen Candida auris (2025) · cites this paper as [35]
The MGCD290 section identifies it as a histone deacetylase 2 (Hos2) inhibitor. It describes a first human trial in severe vulvovaginal candidiasis but does not say MGCD290 was currently in Phase II trials; the Phase II claim is therefore unsupported by our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Amphotericin B has been widely studied and shown to induce antifungal persistence in Candida spp. biofilms and Trichosporon spp.
“Amphotericin B which belongs to polyenes class, due to its potent fungicidal activity and the rarity of resistance [35–37], has been widely studied and shown to induce antifungal persistence in Candida spp. biofilms and Trichosporon spp.”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [35]
The ‘Currently available antifungal drugs’ section (page unavailable) identifies amphotericin B as a polyene and calls it the most potent systemic fungicide in clinical use. The passages found do not report that amphotericin B induces persistence in Candida biofilms or Trichosporon spp.; that part of the claim is unsupported by our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Azole derivatives were developed mostly in the 1980s and 1990s and represent the largest class of antifungal agents used today in clinical medicine.
“Azole derivatives was the next class of antifungals, developed mostly in the 1980s and 1990s [23,24]. They represent the largest class of antifungal agents used today in clinical medicine [35].”
From Antifungal therapy of Candida biofilms: Past, present and future (2023) · cites this paper as [35]
The current arsenal of antifungal compounds used for the treatment of aspergillosis consists of three classes: two target ergosterol, and a third targets β1,3 glucan synthesis.
“The current arsenal of antifungal compounds used for the treatment of aspergillosis consists of three classes of antifungal agents, two of them targeting ergosterol, the functional fungal analogue of cholesterol and the major component specific to fungal membranes, and a third class that targets the synthesis of β1,3 glucan, the major component of the fungal cell wall (610–614) (Fig. 20).”
From Aspergillus fumigatus and Aspergillosis in 2019 (2019) · cites this paper as [614]
In the 1950s, the polyene amphotericin B deoxycholate was the first approved successful antifungal drug.
“In the 1950s, the polyene amphotericin B deoxycholate was the first approved successful antifungal drug [25].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [25]

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“Current antifungal strategies typically target fungal cell membranes, cell walls, and stress response pathways 35 .”
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Authors: Perfect, J. R.
Affiliations: Duke Medical Center (US)
Corresponding author: Perfect, John R.
ORCID: Perfect, John R.
Venue: Nature Reviews Drug Discovery
Publisher: Springer Science and Business Media LLC
Published: 2017-05-12
Volume: 16
Issue: 9
Pages: 603-616
ISSN: 1474-1776 (ISSN-L)
1474-1784
DOI: 10.1038/nrd.2017.46
PMC: PMC5760994
OpenAlex: W2612278270
Cited by: 866
References: 152
Citations by year: 2026: 92 · 2025: 106 · 2024: 103 · 2023: 110 · 2022: 100 · 2021: 108 · 2020: 108 · 2019: 74 · 2018: 50 · 2017: 15
FWCI: 10.46
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Reviews Drug Discovery (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Cidara Therapeutics
National Institute of Allergy and Infectious Diseases (R01AI073896, R01AI093257)
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Keywords: antifungal drug development, invasive fungal infections, immunocompromised patients, polyenes, 5-fluorocytosine, azoles, echinocandins, drug repurposing, antifungal resistance, off-target toxicity
MeSH terms: Invasive Fungal Infections, Animals, Antifungal Agents, Drug Evaluation, Preclinical, Humans, Models, Biological, Drug Resistance, Fungal, Drug Discovery, Molecular Targeted Therapy

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