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Clinical Resistance to Antifungal Mechanism

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A special issue of Journal of Fungi (ISSN 2309-608X). This special issue belongs to the section "Fungal Pathogenesis and Disease Control".

Deadline for manuscript submissions: closed (1 July 2022) | Viewed by 20192

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Special Issue Editors

Dr. Rajendra Prasad

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Guest Editor

Amity Institute of Biotechnology, Amity University Haryana, Haryana, India
Interests: Candida; antifungal resistance; drug transporters; fungal lipidomics; drug resistance evolution; resistance mechanisms
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Anuradha Chowdhary

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Guest Editor

Department of Medical Mycology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
Interests: fungal infections; Candida; Aspergillus; dermatophytes; antifungal resistance
Special Issues, Collections and Topics in MDPI journals

Dr. Dominique Sanglard

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Guest Editor

Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Interests: Candida; Aspergillus; antifungal resistance; fungal pathogenesis

Special Issue Information

Dear Colleagues,

The past two decades have witnessed an exponential rise in fungal infections associated with high mortality and morbidity. The scenario of fungal infections is complicated by the emergence of multidrug resistance (MDR) worldwide. While knowledge on primary antifungal resistance mechanisms in clinically significant fungal pathogens is expanding, a significant proportion of isolates are being reported with unexplained mechanisms hinting toward the involvement of yet unknown resistance mechanisms. The newly emerged fungal pathogen Candida auris has posed a further challenge to clinicians due to its high order of MDR and recently emerged pan-resistant isolates. Given the present situation, studies correlating clinical outcomes based on in vitro resistance patterns and leading to effective antifungal therapy are warranted. In addition, there is an urgent need for extensive high-throughput studies to unveil the underlying major mechanisms of antifungal resistance in fungal isolates. The purpose of this Special Issue of the Journal of Fungi is to address and focus on the concern of antifungal resistance in this current scenario. This Special Issue welcomes contributions on clinical antifungal resistance in fungi and new emerging mechanisms and strategies to combat antifungal resistance. As Guest Editors, we urge authors to share their most recent work in this rapidly growing field. JoF has emerged among top fungal biology journals, hence providing an appropriate forum with a large readership.

Dr. Rajendra Prasad
Prof. Dr. Anuradha Chowdhary
Dr. Dominique Sanglard
Guest Editors

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Keywords

Fungal pathogens
Fungal
Infections
Antifungal resistance
Resistance mechanisms

Published Papers (9 papers)

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Research

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21 pages, 2996 KiB

Open AccessArticle

Voriconazole Treatment Induces a Conserved Sterol/Pleiotropic Drug Resistance Regulatory Network, including an Alternative Ergosterol Biosynthesis Pathway, in the Clinically Important FSSC Species, Fusarium keratoplasticum

by Jasper E. James, Jacinta Santhanam, Richard D. Cannon and Erwin Lamping

J. Fungi 2022, 8(10), 1070; https://doi.org/10.3390/jof8101070 - 12 Oct 2022

Cited by 2 | Viewed by 2276

Abstract

Fusarium keratoplasticum is the Fusarium species most commonly associated with human infections (fusariosis). Antifungal treatment of fusariosis is often hampered by limited treatment options due to resistance towards azole antifungals. The mechanisms of antifungal resistance and sterol biosynthesis in fusaria are poorly understood. Therefore, in this study we assessed the transcriptional response of F. keratoplasticum when exposed to voriconazole. Our results revealed a group of dramatically upregulated ergosterol biosynthesis gene duplicates, most notably erg6A (912-fold), cyp51A (52-fold) and ebp1 (20-fold), which are likely part of an alternative ergosterol biosynthesis salvage pathway. The presence of human cholesterol biosynthesis gene homologs in F. keratoplasticum (ebp1, dhcr7 and dhcr24_1, dhcr24_2 and dhcr24_3) suggests that additional sterol biosynthesis pathways may be induced in fusaria under other growth conditions or during host invasion. Voriconazole also induced the expression of a number of ABC efflux pumps. Further investigations suggested that the highly conserved master regulator of ergosterol biosynthesis, FkSR, and the pleiotropic drug resistance network that induces zinc-cluster transcription factor FkAtrR coordinate the response of FSSC species to azole antifungal exposure. In-depth genome mining also helped clarify the ergosterol biosynthesis pathways of moulds and provided a better understanding of antifungal drug resistance mechanisms in fusaria. Full article

(This article belongs to the Special Issue Clinical Resistance to Antifungal Mechanism)

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14 pages, 2256 KiB

Open AccessArticle

Farnesol Boosts the Antifungal Effect of Fluconazole and Modulates Resistance in Candida auris through Regulation of the CDR1 and ERG11 Genes

by Jaroslava Dekkerová, Lucia Černáková, Samuel Kendra, Elisa Borghi, Emerenziana Ottaviano, Birgit Willinger and Helena Bujdáková

J. Fungi 2022, 8(8), 783; https://doi.org/10.3390/jof8080783 - 27 Jul 2022

Cited by 10 | Viewed by 2119

Abstract

Candida auris is considered a serious fungal pathogen frequently exhibiting a high resistance to a wide range of antifungals. In this study, a combination of the quorum-sensing molecule farnesol (FAR) and fluconazole (FLU) was tested on FLU-resistant C. auris isolates (C. auris S and C. auris R) compared to the susceptible C. auris H261. The aim was to assess the possible synergy between FAR and FLU, by reducing the FLU minimal inhibitory concentration, and to determine the mechanism underlying the conjunct effect. The results confirmed a synergic effect between FAR and FLU with a calculated FIC index of 0.75 and 0.4 for C. auris S and C. auris R, respectively. FAR modulates genes involved in azole resistance. When FAR was added to the cells in combination with FLU, a significant decrease in the expression of the CDR1 gene was observed in the resistant C. auris isolates. FAR seems to block the Cdr1 efflux pump triggering a restoration of the intracellular content of FLU. These results were supported by observed increasing accumulation of rhodamine 6G by C. auris cells. Moreover, C. auris treated with FAR showed an ERG11 gene down-regulation. Overall, these results suggest that FAR is an effective modulator of the Cdr1 efflux pump in C. auris and, in combination with FLU, enhances the activity of this azole, which might be a promising strategy to control infections caused by azole-resistant C. auris. Full article

(This article belongs to the Special Issue Clinical Resistance to Antifungal Mechanism)

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15 pages, 2312 KiB

Open AccessArticle

Digoxin Derivatives Sensitize a Saccharomyces cerevisiae Mutant Strain to Fluconazole by Inhibiting Pdr5p

by Daniel Clemente de Moraes, Ana Claudia Tessis, Rodrigo Rollin-Pinheiro, Jefferson Luiz Princival, José Augusto Ferreira Perez Villar, Leandro Augusto Barbosa, Eliana Barreto-Bergter and Antônio Ferreira-Pereira

J. Fungi 2022, 8(8), 769; https://doi.org/10.3390/jof8080769 - 25 Jul 2022

Cited by 2 | Viewed by 1524

Abstract

The poor outcome of treatments for fungal infections is a consequence of the increasing incidence of resistance to antifungal agents, mainly due to the overexpression of efflux pumps. To surpass this mechanism of resistance, a substance able to inhibit these pumps could be administered in association with antifungals. Saccharomyces cerevisiae possesses an efflux pump (Pdr5p) homologue to those found in pathogenic yeast. Digoxin is a natural product that inhibits Na⁺, K⁺-ATPase. The aim of this study was to evaluate whether digoxin and its derivatives (i.e., DGB, digoxin benzylidene) can inhibit Pdr5p, reversing the resistance to fluconazole in yeasts. An S. cerevisiae mutant strain that overexpresses Pdr5p was used in the assays. The effects of the compounds on yeast growth, efflux activity, and Pdr5p ATPase activity were measured. All derivatives enhanced the antifungal activity of fluconazole against S. cerevisiae, in comparison to fluconazole alone, with FICI values ranging from 0.031 to 0.500. DGB 1 and DGB 3 presented combined effects with fluconazole against a Candida albicans strain, with fractional inhibitory concentration index (FICI) values of 0.625 and 0.281, respectively The compounds also inhibited the efflux of rhodamine 6G and Pdr5p ATPase activity, with IC₅₀ values ranging from 0.41 μM to 3.72 μM. The results suggest that digoxin derivatives impair Pdr5p activity. Considering the homology between Pdr5p and efflux pumps from pathogenic fungi, these compounds are potential candidates to be used in association with fluconazole to treat resistant fungal infections. Full article

(This article belongs to the Special Issue Clinical Resistance to Antifungal Mechanism)

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18 pages, 3147 KiB

Open AccessArticle

Inositol Phosphoryl Transferase, Ipt1, Is a Critical Determinant of Azole Resistance and Virulence Phenotypes in Candida glabrata

by Garima Shahi, Mohit Kumar, Nitesh Kumar Khandelwal, Atanu Banerjee, Parijat Sarkar, Sonam Kumari, Brooke D. Esquivel, Neeraj Chauhan, Amitabha Chattopadhyay, Theodore C. White, Naseem A. Gaur, Ashutosh Singh and Rajendra Prasad

J. Fungi 2022, 8(7), 651; https://doi.org/10.3390/jof8070651 - 21 Jun 2022

Cited by 4 | Viewed by 1843

Abstract

In this study, we have specifically blocked a key step of sphingolipid (SL) biosynthesis in Candida glabrata by disruption of the orthologs of ScIpt1 and ScSkn1. Based on their close homology with S. cerevisiae counterparts, the proteins are predicted to catalyze the addition of a phosphorylinositol group onto mannosyl inositolphosphoryl ceramide (MIPC) to form mannosyl diinositolphosphoryl ceramide (M(IP)₂C), which accounts for the majority of complex SL structures in S. cerevisiae membranes. High throughput lipidome analysis confirmed the accumulation of MIPC structures in ΔCgipt1 and ΔCgskn1 cells, albeit to lesser extent in the latter. Noticeably, ΔCgipt1 cells showed an increased susceptibility to azoles; however, ΔCgskn1 cells showed no significant changes in the drug susceptibility profiles. Interestingly, the azole susceptible phenotype of ΔCgipt1 cells seems to be independent of the ergosterol content. ΔCgipt1 cells displayed altered lipid homeostasis, increased membrane fluidity as well as high diffusion of radiolabeled fluconazole (³H-FLC), which could together influence the azole susceptibility of C. glabrata. Furthermore, in vivo experiments also confirmed compromised virulence of the ΔCgipt1 strain. Contrarily, specific functions of CgSkn1 remain unclear. Full article

(This article belongs to the Special Issue Clinical Resistance to Antifungal Mechanism)

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17 pages, 1844 KiB

Open AccessArticle

Characterization of the Candida glabrata Transcription Factor CgMar1: Role in Azole Susceptibility

by Pedro Pais, Mónica Galocha, Raquel Califórnia, Romeu Viana, Mihaela Ola, Michiyo Okamoto, Hiroji Chibana, Geraldine Butler and Miguel C. Teixeira

J. Fungi 2022, 8(1), 61; https://doi.org/10.3390/jof8010061 - 07 Jan 2022

Viewed by 2298

Abstract

The prevalence of antifungal resistance in Candida glabrata, especially against azole drugs, results in difficult-to-treat and potentially life-threatening infections. Understanding the molecular basis of azole resistance in C. glabrata is crucial to designing more suitable therapeutic strategies. In this study, the role of the transcription factor encoded by ORF CAGL0B03421g, here denominated as CgMar1 (Multiple Azole Resistance 1), in azole susceptibility was explored. Using RNA-sequencing, CgMar1 was found to regulate 337 genes under fluconazole stress, including several related to lipid biosynthesis pathways. In this context, CgMar1 and its target CgRSB1, encoding a predicted sphingoid long-chain base efflux transporter, were found to contribute to plasma membrane sphingolipid incorporation and membrane permeability, decreasing fluconazole accumulation. CgMar1 was found to associate with the promoter of CgRSB1, which contains two instances of the CCCCTCC consensus, found to be required for CgRSB1 activation during fluconazole stress. Altogether, a regulatory pathway modulating azole susceptibility in C. glabrata is proposed, resulting from what appears to be a neofunctionalization of a Hap1-like transcription factor. Full article

(This article belongs to the Special Issue Clinical Resistance to Antifungal Mechanism)

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12 pages, 5061 KiB

Open AccessArticle

In Vivo Efficacy of Voriconazole in a Galleria mellonella Model of Invasive Infection Due to Azole-Susceptible or Resistant Aspergillus fumigatus Isolates

by Sana Jemel, Jacques Guillot, Kalthoum Kallel, Grégory Jouvion, Elise Brisebard, Eliane Billaud, Vincent Jullien, Françoise Botterel and Eric Dannaoui

J. Fungi 2021, 7(12), 1012; https://doi.org/10.3390/jof7121012 - 26 Nov 2021

Cited by 5 | Viewed by 1717

Abstract

Aspergillus fumigatus is an environmental filamentous fungus responsible for life-threatening infections in humans and animals. Azoles are the first-line treatment for aspergillosis, but in recent years, the emergence of azole resistance in A. fumigatus has changed treatment recommendations. The objective of this study was to evaluate the efficacy of voriconazole (VRZ) in a Galleria mellonella model of invasive infection due to azole-susceptible or azole-resistant A. fumigatus isolates. We also sought to describe the pharmacokinetics of VRZ in the G. mellonella model. G. mellonella larvae were infected with conidial suspensions of azole-susceptible and azole-resistant isolates of A. fumigatus. Mortality curves were used to calculate the lethal dose. Assessment of the efficacy of VRZ or amphotericin B (AMB) treatment was based on mortality in the lethal model and histopathologic lesions. The pharmacokinetics of VRZ were determined in larval hemolymph. Invasive fungal infection was obtained after conidial inoculation. A dose-dependent reduction in mortality was observed after antifungal treatment with AMB and VRZ. VRZ was more effective at treating larvae inoculated with azole-susceptible A. fumigatus isolates than larvae inoculated with azole-resistant isolates. The concentration of VRZ was maximal at the beginning of treatment and gradually decreased in the hemolymph to reach a C_min (24 h) between 0.11 and 11.30 mg/L, depending on the dose. In conclusion, G. mellonella is a suitable model for testing the efficacy of antifungal agents against A. fumigatus. Full article

(This article belongs to the Special Issue Clinical Resistance to Antifungal Mechanism)

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14 pages, 11350 KiB

Open AccessArticle

Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae

by Valentin Borgeat, Danielle Brandalise, Frédéric Grenouillet and Dominique Sanglard

J. Fungi 2021, 7(9), 760; https://doi.org/10.3390/jof7090760 - 15 Sep 2021

Cited by 12 | Viewed by 2446

Abstract

Candida lusitaniae is an opportunistic pathogen in humans that causes infrequent but difficult-to-treat diseases. Antifungal drugs are used in the clinic to treat C. lusitaniae infections, however, this fungus can rapidly acquire antifungal resistance to all known antifungal drugs (multidrug resistance). C. lusitaniae acquires azole resistance by gain-of-function (GOF) mutations in the transcriptional regulator MRR1. MRR1 controls the expression of a major facilitator transporter (MFS7) that is important for fluconazole resistance. Here, we addressed the role of the ATP Binding Cassette (ABC) transporter CDR1 as additional mediator of azole resistance in C. lusitaniae. CDR1 expression in isolates with GOF MRR1 mutations was higher compared to wild types, which suggests that CDR1 is an additional (direct or indirect) target of MRR1. CDR1 deletion in the azole-resistant isolate P3 (V688G GOF) revealed that MICs of long-tailed azoles, itraconazole and posaconazole, were decreased compared to P3, which is consistent with the role of this ABC transporter in the efflux of these azoles. Fluconazole MIC was only decreased when CDR1 was deleted in the background of an mfs7Δ mutant from P3, which underpins the dominant role of MFS7 in the resistance of the short-tailed azole fluconazole. With R6G efflux readout as Cdr1 efflux capacity, our data showed that R6G efflux was increased in P3 compared to an azole-susceptible wild type parent, and diminished to background levels in mutant strains lacking CDR1. Milbemycin oxim A3, a known inhibitor of fungal ABC transporters, mimicked efflux phenotypes of cdr1Δ mutants. We therefore provided evidence that CDR1 is an additional mediator of azole resistance in C. lusitaniae, and that CDR1 regulation is dependent on MRR1 and associated GOF mutations. Full article

(This article belongs to the Special Issue Clinical Resistance to Antifungal Mechanism)

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16 pages, 13492 KiB

Open AccessReview

Epigenetic Regulation of Antifungal Drug Resistance

by Sandip Patra, Mayur Raney, Aditi Pareek and Rupinder Kaur

J. Fungi 2022, 8(8), 875; https://doi.org/10.3390/jof8080875 - 19 Aug 2022

Cited by 3 | Viewed by 3184

Abstract

In medical mycology, epigenetic mechanisms are emerging as key regulators of multiple aspects of fungal biology ranging from development, phenotypic and morphological plasticity to antifungal drug resistance. Emerging resistance to the limited therapeutic options for the treatment of invasive fungal infections is a growing concern. Human fungal pathogens develop drug resistance via multiple mechanisms, with recent studies highlighting the role of epigenetic changes involving the acetylation and methylation of histones, remodeling of chromatin and heterochromatin-based gene silencing, in the acquisition of antifungal resistance. A comprehensive understanding of how pathogens acquire drug resistance will aid the development of new antifungal therapies as well as increase the efficacy of current antifungals by blocking common drug-resistance mechanisms. In this article, we describe the epigenetic mechanisms that affect resistance towards widely used systemic antifungal drugs: azoles, echinocandins and polyenes. Additionally, we review the literature on the possible links between DNA mismatch repair, gene silencing and drug-resistance mechanisms. Full article

(This article belongs to the Special Issue Clinical Resistance to Antifungal Mechanism)

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7 pages, 409 KiB

Open AccessCase Report

Pan-Echinocandin Resistant C. parapsilosis Harboring an F652S Fks1 Alteration in a Patient with Prolonged Echinocandin Therapy

by Maria Siopi, Antonios Papadopoulos, Anastasia Spiliopoulou, Fotini Paliogianni, Nissrine Abou-Chakra, Maiken Cavling Arendrup, Christina Damoulari, Georgios Tsioulos, Efthymia Giannitsioti, Frantzeska Frantzeskaki, Iraklis Tsangaris, Spyros Pournaras and Joseph Meletiadis

J. Fungi 2022, 8(9), 931; https://doi.org/10.3390/jof8090931 - 01 Sep 2022

Cited by 14 | Viewed by 1500

Abstract

The isolation of a pan-echinocandin-resistant Candida parapsilosis strain (anidulafungin, caspofungin, micafungin and rezafungin EUCAST MICs > 8 mg/L) from urine of a patient following prolonged exposure to echinocandins (38 days of micafungin followed by 16 days of anidulafungin) is described. The isolate harbored the novel alteration F652S in the hotspot 1 region of fks1. Isogenic C. parapsilosis bloodstream isolates collected up to 1.5 months earlier from the same patient were susceptible to echinocandins (anidulafungin, caspofungin and micafungin EUCAST MICs 1–2, 1 and 1 mg/L, respectively) and contained wild-type FKS1 sequences. This is the first report of pan-echinocandin resistance in C. parapsilosis associated with an aminoacid change in hotspot 1 region of fks1. Full article

(This article belongs to the Special Issue Clinical Resistance to Antifungal Mechanism)

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