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      Disclosing azole resistance mechanisms in resistant Candida glabrata strains encoding wild-type or gain-of-function CgPDR1 alleles through comparative genomics and transcriptomics

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          Abstract

          The pathogenic yeast Candida glabrata is intrinsically resilient to azoles and rapidly acquires resistance to these antifungals, in vitro and in vivo. In most cases azole-resistant C. glabrata clinical strains encode hyperactive CgPdr1 variants, however, resistant strains encoding wild-type CgPDR1 alleles have also been isolated, although remaining to be disclosed the underlying resistance mechanism. In this study, we scrutinized the mechanisms underlying resistance to azoles of 8 resistant clinical C. glabrata strains, identified along the course of epidemiological surveys undertaken in Portugal. Seven of the strains were found to encode CgPdr1 gain-of-function variants (I392M, E555K, G558C, and I803T) with the substitutions I392M and I803T being herein characterized as hyper-activating mutations for the first time. While cells expressing the wild-type CgPDR1 allele required the mediator subunit Gal11A to enhance tolerance to fluconazole, this was dispensable for cells expressing the I803T variant indicating that the CgPdr1 interactome is shaped by different gain-of-function substitutions. Genomic and transcriptomic profiling of the sole azole-resistant C. glabrata isolate encoding a wild-type CgPDR1 allele (ISTB218) revealed that under fluconazole stress this strain over-expresses various genes described to provide protection against this antifungal, while also showing reduced expression of genes described to increase sensitivity to these drugs. The overall role in driving the azole-resistance phenotype of the ISTB218 C. glabrata isolate played by these changes in the transcriptome and genome of the ISTB218 isolate are discussed shedding light into mechanisms of resistance that go beyond the CgPdr1-signalling pathway and that may alone, or in combination, pave the way for the acquisition of resistance to azoles in vivo.

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          Global and Multi-National Prevalence of Fungal Diseases—Estimate Precision

          Fungal diseases kill more than 1.5 million and affect over a billion people. However, they are still a neglected topic by public health authorities even though most deaths from fungal diseases are avoidable. Serious fungal infections occur as a consequence of other health problems including asthma, AIDS, cancer, organ transplantation and corticosteroid therapies. Early accurate diagnosis allows prompt antifungal therapy; however this is often delayed or unavailable leading to death, serious chronic illness or blindness. Recent global estimates have found 3,000,000 cases of chronic pulmonary aspergillosis, ~223,100 cases of cryptococcal meningitis complicating HIV/AIDS, ~700,000 cases of invasive candidiasis, ~500,000 cases of Pneumocystis jirovecii pneumonia, ~250,000 cases of invasive aspergillosis, ~100,000 cases of disseminated histoplasmosis, over 10,000,000 cases of fungal asthma and ~1,000,000 cases of fungal keratitis occur annually. Since 2013, the Leading International Fungal Education (LIFE) portal has facilitated the estimation of the burden of serious fungal infections country by country for over 5.7 billion people (>80% of the world’s population). These studies have shown differences in the global burden between countries, within regions of the same country and between at risk populations. Here we interrogate the accuracy of these fungal infection burden estimates in the 43 published papers within the LIFE initiative.
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            Invasive candidiasis

            Invasive candidiasis is an important health-care-associated fungal infection that can be caused by several Candida spp.; the most common species is Candida albicans, but the prevalence of these organisms varies considerably depending on geographical location. The spectrum of disease of invasive candidiasis ranges from minimally symptomatic candidaemia to fulminant sepsis with an associated mortality exceeding 70%. Candida spp. are common commensal organisms in the skin and gut microbiota, and disruptions in the cutaneous and gastrointestinal barriers (for example, owing to gastrointestinal perforation) promote invasive disease. A deeper understanding of specific Candida spp. virulence factors, host immune response and host susceptibility at the genetic level has led to key insights into the development of early intervention strategies and vaccine candidates. The early diagnosis of invasive candidiasis is challenging but key to the effective management, and the development of rapid molecular diagnostics could improve the ability to intervene rapidly and potentially reduce mortality. First-line drugs, including echinocandins and azoles, are effective, but the emergence of antifungal resistance, especially among Candida glabrata, is a matter of concern and underscores the need to administer antifungal medications in a judicious manner, avoiding overuse when possible. A newly described pathogen, Candida auris, is an emerging multidrug-resistant organism that poses a global threat.
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              Twenty Years of the SENTRY Antifungal Surveillance Program: Results for Candida Species From 1997–2016

              Abstract Background The emergence of antifungal resistance threatens effective treatment of invasive fungal infection (IFI). Invasive candidiasis is the most common health care–associated IFI. We evaluated the activity of fluconazole (FLU) against 20 788 invasive isolates of Candida (37 species) collected from 135 medical centers in 39 countries (1997–2016). The activity of anidulafungin, caspofungin, and micafungin (MCF) was evaluated against 15 308 isolates worldwide (2006–2016). Methods Species identification was accomplished using phenotypic (1997–2001), genotypic, and proteomic methods (2006–2016). All isolates were tested using reference methods and clinical breakpoints published in the Clinical and Laboratory Standards Institute documents. Results A decrease in the isolation of Candida albicans and an increase in the isolation of Candida glabrata and Candida parapsilosis were observed over time. Candida glabrata was the most common non–C. albicans species detected in all geographic regions except for Latin America, where C. parapsilosis and Candida tropicalis were more common. Six Candida auris isolates were detected: 1 each in 2009, 2013, 2014, and 2015 and 2 in 2016; all were from nosocomial bloodstream infections and were FLU-resistant (R). The highest rates of FLU-R isolates were seen in C. glabrata from North America (NA; 10.6%) and in C. tropicalis from the Asia-Pacific region (9.2%). A steady increase in isolation of C. glabrata and resistance to FLU was detected over 20 years in the United States. Echinocandin-R (EC-R) ranged from 3.5% for C. glabrata to 0.1% for C. albicans and C. parapsilosis. Resistance to MCF was highest among C. glabrata (2.8%) and C. tropicalis (1.3%) from NA. Mutations on FKS hot spot (HS) regions were detected among 70 EC-R isolates (51/70 were C. glabrata). Most isolates harboring FKS HS mutations were resistant to 2 or more ECs. Conclusions EC-R and FLU-R remain uncommon among contemporary Candida isolates; however, a slow and steady emergence of resistance to both antifungal classes was observed in C. glabrata and C. tropicalis isolates.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                G3 (Bethesda)
                Genetics
                g3journal
                G3: Genes|Genomes|Genetics
                Oxford University Press
                2160-1836
                July 2022
                09 May 2022
                09 May 2022
                : 12
                : 7
                : jkac110
                Affiliations
                iBB, Institute for Bioengineering and Biosciences, Instituto Superior Técnico—Department of Bioengineering, Universidade de Lisboa , Lisboa 1049-001, Portugal
                Associate Laboratory i4HB—Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa , Lisboa 1049-001, Portugal
                iBB, Institute for Bioengineering and Biosciences, Instituto Superior Técnico—Department of Bioengineering, Universidade de Lisboa , Lisboa 1049-001, Portugal
                Associate Laboratory i4HB—Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa , Lisboa 1049-001, Portugal
                iBB, Institute for Bioengineering and Biosciences, Instituto Superior Técnico—Department of Bioengineering, Universidade de Lisboa , Lisboa 1049-001, Portugal
                Associate Laboratory i4HB—Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa , Lisboa 1049-001, Portugal
                Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro , Aveiro 3810, Portugal
                Departamento de Microbiologia e Imunologia, Faculdade de Farmácia da Universidade de Lisboa , Lisboa 1649-003, Portugal
                Laboratório de Microbiologia, Hospital Dona Estefânia (Centro Hospitalar Universitário Lisboa Central) , Lisboa 1169-045, Portugal
                Seção de Microbiologia, Laboratório SYNLAB—Lisboa, Grupo SYNLAB Portugal , Lisboa 1070-061, Portugal
                iBB, Institute for Bioengineering and Biosciences, Instituto Superior Técnico—Department of Bioengineering, Universidade de Lisboa , Lisboa 1049-001, Portugal
                Associate Laboratory i4HB—Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa , Lisboa 1049-001, Portugal
                iBB, Institute for Bioengineering and Biosciences, Instituto Superior Técnico—Department of Bioengineering, Universidade de Lisboa , Lisboa 1049-001, Portugal
                Associate Laboratory i4HB—Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa , Lisboa 1049-001, Portugal
                Author notes
                Corresponding author: Department of Bioengineering, iBB, Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001, Lisboa, Portugal. Email: nuno.mira@ 123456tecnico.ulisboa.pt
                Author information
                https://orcid.org/0000-0002-4867-8975
                https://orcid.org/0000-0003-4000-7461
                https://orcid.org/0000-0001-9112-265X
                https://orcid.org/0000-0001-7556-0385
                Article
                jkac110
                10.1093/g3journal/jkac110
                9258547
                35532173
                e7109020-ec3f-4ae8-a47a-b701e179e41d
                © The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 09 September 2021
                : 25 April 2022
                : 18 May 2022
                Page count
                Pages: 14
                Funding
                Funded by: FCT—Fundação para a Ciência e a Tecnologia;
                Award ID: UIDB/04565/2020
                Funded by: Research Unit Institute for Bioengineering and Biosciences—iBB;
                Award ID: LA/P/0140/2020
                Funded by: Associate Laboratory Institute for Health and Bioeconomy—i4HB;
                Categories
                Fungal Genetics and Genomics
                AcademicSubjects/SCI01180
                AcademicSubjects/SCI01140
                AcademicSubjects/SCI00010
                AcademicSubjects/SCI00960

                Genetics
                cgpdr1,cgpdr1-dependent and independent azole-resistance,azole resistance,candida glabrata

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