Multidrug-Resistant Fungi

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 (31 March 2024) | Viewed by 12637

Special Issue Editors


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Guest Editor
Laboratório de Bioquímica Microbiana, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
Interests: multidrug resistance; fungi; antifungal; efflux pumps; ATPase

E-Mail Website
Guest Editor
Laboratório de Bioquímica Microbiana, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
Interests: antifungal resistance; biofilms; efflux pumps; yeasts

Special Issue Information

Dear Colleagues,

The multidrug resistance (MDR) phenotype is the major factor responsible for the failure of antifungal therapy, increasing the length of hospital stay, treatment´s cost, and death rate. The main mechanisms of antifungal resistance are related to: 1) the presence of transporter proteins in the plasma membrane, extruding drugs from the intracellular milieu and therefore preventing them from reaching the necessary concentration which would allow them to be effective against the fungi; and 2) biofilm production. Nonetheless, other mechanisms may be observed, such as point mutations at ERG11 and FKS. Due to the importance of MDR to public health, the discovery of new molecules able to inhibit efflux transporters and/or disrupt biofilms emerges as a promising strategy for strengthening the antifungal arsenal. This Special Issue aims to feature and promote research regarding drugs that block the multidrug resistance phenotype.

Prof. Dr. Antônio Ferreira-Pereira
Prof. Dr. Daniel Clemente de Moraes
Guest Editors

Manuscript Submission Information

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Keywords

  • antimicrobial resistance
  • efflux pumps
  • multidrug resistance
  • antifungal

Published Papers (5 papers)

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Research

15 pages, 3092 KiB  
Article
Importance of the Aspergillus fumigatus Mismatch Repair Protein Msh6 in Antifungal Resistance Development
by Jose Lucio, Irene Gonzalez-Jimenez, Alejandra Roldan, Jorge Amich, Laura Alcazar-Fuoli and Emilia Mellado
J. Fungi 2024, 10(3), 210; https://doi.org/10.3390/jof10030210 - 12 Mar 2024
Viewed by 1073
Abstract
One of the systems responsible for the recognition and repair of mistakes occurring during cell replication is the DNA mismatch repair (MMR) system. Two major protein complexes constitute the MMR pathway: MutS and MutL. Here, we investigated the possible relation of four A. [...] Read more.
One of the systems responsible for the recognition and repair of mistakes occurring during cell replication is the DNA mismatch repair (MMR) system. Two major protein complexes constitute the MMR pathway: MutS and MutL. Here, we investigated the possible relation of four A. fumigatus MMR genes (msh2, msh6, pms1, and mlh1) with the development of azole resistance related to the phenomenon of multi-drug resistance. We examined the MMR gene variations in 163 Aspergillus fumigatus genomes. Our analysis showed that genes msh2, pms1, and mlh1 have low genetic variability and do not seem to correlate with drug resistance. In contrast, there is a nonsynonymous mutation (G240A) in the msh6 gene that is harbored by 42% of the strains, most of them also harboring the TR34/L98H azole resistance mechanism in cyp51A. The msh6 gene was deleted in the akuBKU80 A. fumigatus strain, and the ∆msh6 isolates were analyzed for fitness, azole susceptibility, and virulence capacity, showing no differences compared with the akuBKU80 parental strain. Wild-type msh6 and Δmsh6 strains were grown on high concentrations of azole and other non-azole fungicides used in crop protection. A 10- and 2-fold higher mutation frequency in genes that confer resistance to boscalid and benomyl, respectively, were observed in Δmsh6 strains compared to the wild-type. This study suggests a link between Msh6 and fungicide resistance acquisition. Full article
(This article belongs to the Special Issue Multidrug-Resistant Fungi)
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18 pages, 4241 KiB  
Article
Miltefosine: A Repurposing Drug against Mucorales Pathogens
by Mariana Ingrid Dutra da Silva Xisto, Rodrigo Rollin-Pinheiro, Victor Pereira Rochetti, Yuri de Castro-Almeida, Luana Pereira Borba-Santos, Giulia Maria Pires dos Santos-Freitas, Jefferson Cypriano, Fernanda de Ávila Abreu, Sonia Rozental and Eliana Barreto-Bergter
J. Fungi 2023, 9(12), 1166; https://doi.org/10.3390/jof9121166 - 04 Dec 2023
Cited by 1 | Viewed by 1097
Abstract
Mucorales are a group of non-septated filamentous fungi widely distributed in nature, frequently associated with human infections, and are intrinsically resistant to many antifungal drugs. For these reasons, there is an urgent need to improve the clinical management of mucormycosis. Miltefosine, which is [...] Read more.
Mucorales are a group of non-septated filamentous fungi widely distributed in nature, frequently associated with human infections, and are intrinsically resistant to many antifungal drugs. For these reasons, there is an urgent need to improve the clinical management of mucormycosis. Miltefosine, which is a phospholipid analogue of alkylphosphocholine, has been considered a promising repurposing drug to be used to treat fungal infections. In the present study, miltefosine displayed antifungal activity against a variety of Mucorales species, and it was also active against biofilms formed by these fungi. Treatment with miltefosine revealed modifications of cell wall components, neutral lipids, mitochondrial membrane potential, cell morphology, and the induction of oxidative stress. Treated Mucorales cells also presented an increased susceptibility to SDS. Purified ergosterol and glucosylceramide added to the culture medium increased miltefosine MIC, suggesting its interaction with fungal lipids. These data contribute to elucidating the effect of a promising drug repurposed to act against some relevant fungal pathogens that significantly impact public health. Full article
(This article belongs to the Special Issue Multidrug-Resistant Fungi)
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29 pages, 7277 KiB  
Article
The Transcriptome Response to Azole Compounds in Aspergillus fumigatus Shows Differential Gene Expression across Pathways Essential for Azole Resistance and Cell Survival
by Margriet W. J. Hokken, Jordy P. M. Coolen, Hilbert Steenbreker, Jan Zoll, Tim J. H. Baltussen, Paul E. Verweij and Willem J. G. Melchers
J. Fungi 2023, 9(8), 807; https://doi.org/10.3390/jof9080807 - 30 Jul 2023
Cited by 1 | Viewed by 1160
Abstract
The opportunistic pathogen Aspergillus fumigatus is found on all continents and thrives in soil and agricultural environments. Its ability to readily adapt to novel environments and to produce billions of spores led to the spread of azole-resistant A. fumigatus across the globe, posing [...] Read more.
The opportunistic pathogen Aspergillus fumigatus is found on all continents and thrives in soil and agricultural environments. Its ability to readily adapt to novel environments and to produce billions of spores led to the spread of azole-resistant A. fumigatus across the globe, posing a threat to many immunocompromised patients, including critically ill patients with severe influenza or COVID-19. In our study, we sought to compare the adaptational response to azoles from A. fumigatus isolates that differ in azole susceptibility and genetic background. To gain more insight into how short-term adaptation to stressful azole compounds is managed through gene expression, we conducted an RNA-sequencing study on the response of A. fumigatus to itraconazole and the newest clinically approved azole, isavuconazole. We observed many similarities in ergosterol biosynthesis up-regulation across isolates, with the exception of the pan-azole-resistant isolate, which showed very little differential regulation in comparison to other isolates. Additionally, we found differential regulation of membrane efflux transporters, secondary metabolites, iron metabolism, and various stress response and cell signaling mechanisms. Full article
(This article belongs to the Special Issue Multidrug-Resistant Fungi)
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17 pages, 1904 KiB  
Article
Synthesis of Altissimacoumarin D and Other Prenylated Coumarins and Their Ability to Reverse the Multidrug Resistance Phenotype in Candida albicans
by Anna Claudia Silva, Daniel Clemente de Moraes, Denilson Costa do Carmo, Giselle Cristina Casaes Gomes, A. Ganesan, Rosangela Sabbatini Capella Lopes, Antonio Ferreira-Pereira and Cláudio Cerqueira Lopes
J. Fungi 2023, 9(7), 758; https://doi.org/10.3390/jof9070758 - 18 Jul 2023
Viewed by 889
Abstract
Azoles are the main antifungal agents employed in clinical practice to treat invasive candidiasis. Nonetheless, their efficacy is limited by fungal resistance mechanisms, mainly the overexpression of efflux pumps. Consequently, candidiasis has a worrisome death rate of 75%. One potential strategy to overcome [...] Read more.
Azoles are the main antifungal agents employed in clinical practice to treat invasive candidiasis. Nonetheless, their efficacy is limited by fungal resistance mechanisms, mainly the overexpression of efflux pumps. Consequently, candidiasis has a worrisome death rate of 75%. One potential strategy to overcome efflux-mediated resistance is to inhibit this process. Ailanthus altissima is a Chinese tree that produces several active substances, including altissimacoumarin D. Due to the low yield of its extraction and the need to search for new drugs to treat candidiasis, this study aimed to synthesize altissimacoumarin D and its analogues, as well as evaluating their ability to reverse the resistance phenotype of Candida albicans. Coumarin isofraxidin was prepared via total synthesis through a solvent-free Knoevenagel condensation as the key step. Isofraxidin and other commercially available coumarins were alkylated with prenyl or geranyl groups to yield the natural product altissimacoumarin D and seven analogues. The antifungal activity of the coumarins and their ability to reverse the fungal resistance phenotype were assessed using microbroth methodologies. Toxicity was evaluated using erythrocytes and an in silico prediction. All compounds improved the antifungal activity of fluconazole by inhibiting efflux pumps, and ACS47 and ACS50 were the most active. None of the coumarins were toxic to erythrocytes. In silico predictions indicate that ACS47 and ACS50 may be safe for human use. ACS47 and ACS50 are promising candidates when used as adjuvants in the antifungal therapy against C. albicans-resistant strains. Full article
(This article belongs to the Special Issue Multidrug-Resistant Fungi)
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9 pages, 1652 KiB  
Article
Candida auris in Dog Ears
by Anamika Yadav, Yue Wang, Kusum Jain, Vijay Amrit Raj Panwar, Hardeep Kaur, Vikas Kasana, Jianping Xu and Anuradha Chowdhary
J. Fungi 2023, 9(7), 720; https://doi.org/10.3390/jof9070720 - 30 Jun 2023
Cited by 6 | Viewed by 7773
Abstract
Candida auris is an emerging global public health threat and is resistant to most antifungal agents. Though fungi are significant pathogens for animals, the role of C. auris in animal health remains unexplored. Here, we analysed the microbial cultures of skin and ear [...] Read more.
Candida auris is an emerging global public health threat and is resistant to most antifungal agents. Though fungi are significant pathogens for animals, the role of C. auris in animal health remains unexplored. Here, we analysed the microbial cultures of skin and ear swabs of 87 dogs in Delhi and performed fungal meta-barcode sequencing of ear and skin samples of 7 dogs with confirmed otitis externa (OE). Overall, 4.5% of dogs (4/87) with chronic skin infections contained evidence of C. auris in their ear canal (n = 3) and on their skin surface (n = 1). Of the three OE dogs with C. auris infection/colonisation, a diversity of fungi was observed, and their meta-barcode ITS sequence reads for C. auris ranged from 0.06% to 0.67%. Whole-genome sequencing of six C. auris strains obtained in culture from two dogs showed relatedness with Clade I clinical strains. The report highlights the isolation of C. auris from an animal source; however, the routes of transmission of this yeast to dogs and the clinical significance of transmission between dogs and humans remain to be investigated. Full article
(This article belongs to the Special Issue Multidrug-Resistant Fungi)
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