Intrinsic short-tailed azole resistance in mucormycetes is due to an evolutionary conserved aminoacid substitution of the lanosterol 14α-demethylase

Caramalho, Rita; Tyndall, Joel D. A.; Monk, Brian C.; Larentis, Thomas; Lass‐Flörl, Cornelia; Lackner, Michaela

doi:10.1038/s41598-017-16123-9

Cited by 68 publications

(92 citation statements)

References 58 publications

(84 reference statements)

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“…Mucoralean species are the causative agents of mucormycosis, an emerging fungal infection with extremely poor clinical outcomes, probably as a consequence of their innate resistance to all current antifungal drugs [28,29] and their ability to evade host innate immunity [30,31]. In spite of their clinical relevance, limited information is available on essential biological processes in these fungal pathogens, especially nuclear division and the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Early Diverging Fungus Mucor circinelloides Lacks Centromeric Histone CENP-A and Displays a Mosaic of Point and Regional Centromeres

et al. 2019

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Section: Discussionmentioning

confidence: 99%

Early Diverging Fungus Mucor circinelloides Lacks Centromeric Histone CENP-A and Displays a Mosaic of Point and Regional Centromeres

et al. 2019

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“…Mucoralean species are the causative agents of mucormycosis, an emerging fungal infection with extremely poor clinical outcomes, probably as a consequence of their innate resistance to all current antifungal drugs 27,28 and their ability to evade host innate immunity 29,30 . In spite of their clinical relevance, limited information is available on essential biological processes in these fungal pathogens, especially nuclear division and cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Early diverging fungus Mucor circinelloides lacks centromeric histone CENP-A and displays a mosaic of point and regional centromeres

Navarro-Mendoza

Pérez-Arques

Panchal

et al. 2019

Preprint

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15Centromeres are rapidly evolving across eukaryotes, despite performing a conserved 16 function to ensure high fidelity chromosome segregation. CENP-A chromatin is a hallmark of 17 a functional centromere in most organisms. Due to its critical role in kinetochore architecture, 18 the loss of CENP-A is tolerated in only a few organisms, many of which possess holocentric 19 chromosomes. Here, we characterize the consequence of the loss of CENP-A in the fungal 20 kingdom. Mucor circinelloides, an opportunistic human pathogen, lacks CENP-A along with 21 the evolutionarily conserved CENP-C, but assembles a monocentric chromosome with a 22 localized kinetochore complex throughout the cell cycle. Mis12 and Dsn1, two conserved 23 kinetochore proteins were found to bind nine short overlapping regions, each comprising an 24 2 ~200-bp AT-rich sequence followed by a centromere-specific conserved motif that echoes the 25 structure of budding yeast point centromeres. Resembling fungal regional centromeres, these 26 core centromere regions are embedded in large genomic expanses devoid of genes yet marked 27 by Grem-LINE1s, a novel retrotransposable element silenced by the Dicer-dependent RNAi 28 pathway. Our results suggest that these hybrid features of point and regional centromeres arose 29 from the absence of CENP-A, thus defining novel mosaic centromeres in this early-diverging 30 fungus. 31 Introduction 32Accurate chromosome segregation is crucial to maintain genome integrity during cell 33 division. The timely attachment of microtubules to centromere DNA is essential to achieve 34proper chromosome segregation. This is accomplished by a specialized multilayered protein 35 complex, the kinetochore which links microtubules to centromere DNA. This protein bridge is 36 divided into two layersthe inner and outer kinetochore. The fundamental inner kinetochore 37 protein is the histone H3 variant CENP-A. It binds directly to centromere DNA and lays the 38 foundation to recruit other essential proteins of the kinetochore complex, playing a fundamental 39 role in centromere structure and function, and hence, precise chromosome segregation 1,2 . 40 CENP-A is also found at all identified neocentromeres 3 and at the active centromeres of 41 dicentric chromosomes 4 , acting as an epigenetic determinant of centromeric identity. 42Despite its conserved function, the centromere is one of the most rapidly evolving 43 regions of the genome 5 . This so-called "centromere paradox" has led to centromeres of diverse 44 sizes and content. The first centromeres identified in Saccharomyces cerevisiae were found to 45 be point centromeres -small regions of ~120 bp defined by specific DNA sequences 6,7 . In 46 contrast to point centromeres described in only a few budding yeasts of the phylum 47 Ascomycota, most other fungi and metazoans have regional centromeres that are larger, 48 ranging from a few kilobases to several megabases 8 . Regional centromeres are often 49 3 interspersed with repetitive sequences and are mostly defined by epigenetic fac...

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“…Treatment of mucormycosis is difficult because of the intrinsic resistance of Mucorales against echinocandins (22,23) and voriconazole (24)(25)(26). In contrast to classical views in the literature, the response against the remaining antifungal drugs is not homogeneous within the Mucorales.…”

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confidence: 92%

A Revised Species Concept for OpportunisticMucorSpecies Reveals Species-Specific Antifungal Susceptibility Profiles

Wagner

Hoog

Alastruey‐Izquierdo

et al. 2019

Antimicrob Agents Chemother

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Recently, the species concept of opportunistic Mucor circinelloides and its relatives has been revised, resulting in the recognition of its classical formae as independent species and the description of new species. In this study, we used isolates of all clinically relevant Mucor species and performed susceptibility testing using the EUCAST reference method to identify potential species-specific susceptibility patterns. In vitro susceptibility profiles of 101 mucoralean strains belonging to the genus Mucor (72), the closely related species Cokeromyces recurvatus (3), Rhizopus (12), Lichtheimia (10), and Rhizomucor (4) to six antifungals (amphotericin B, natamycin, terbinafine, isavuconazole, itraconazole, and posaconazole) were determined. The most active drug for all Mucorales was amphotericin B. Antifungal susceptibility profiles of pathogenic Mucor species were specific for isavuconazole, itraconazole, and posaconazole. The species formerly united in M. circinelloides showed clear differences in their antifungal susceptibilities. Cokeromyces recurvatus, Mucor ardhlaengiktus, Mucor lusitanicus (M. circinelloides f. lusitanicus), and Mucor ramosissimus exhibited high MICs to all azoles tested. Mucor indicus presented high MICs for isavuconazole and posaconazole, and Mucor amphibiorum and Mucor irregularis showed high MICs for isavuconazole. MIC values of Mucor spp. for posaconazole, isavuconazole, and itraconazole were high compared to those for Rhizopus and the Lichtheimiaceae (Lichtheimia and Rhizomucor). Molecular identification combined with in vitro susceptibility testing is recommended for Mucor species, especially if azoles are applied in treatment.

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Intrinsic short-tailed azole resistance in mucormycetes is due to an evolutionary conserved aminoacid substitution of the lanosterol 14α-demethylase

Cited by 68 publications

References 58 publications

Early Diverging Fungus Mucor circinelloides Lacks Centromeric Histone CENP-A and Displays a Mosaic of Point and Regional Centromeres

Early Diverging Fungus Mucor circinelloides Lacks Centromeric Histone CENP-A and Displays a Mosaic of Point and Regional Centromeres

Early diverging fungus Mucor circinelloides lacks centromeric histone CENP-A and displays a mosaic of point and regional centromeres

A Revised Species Concept for OpportunisticMucorSpecies Reveals Species-Specific Antifungal Susceptibility Profiles

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