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

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

doi:10.3390/jof8070651

Cited by 5 publications

(2 citation statements)

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“…Oligomycin and Pdr1 therefore conferred micafungin resistance through other target(s). One target of Pdr1 that contributed to micafungin resistance in this study is IPT1 , which promotes biosynthesis of a sphingolipid (Shahi et al 2022). On the other hand, CDR1 and its paralog PDH1 may have the opposite effect as transposon insertions in these genes increased competitive fitness in micafungin.…”

Section: Discussionmentioning

confidence: 95%

Tn-seq of theCandida glabratareference strain CBS138 reveals epigenetic plasticity, structural variation, and intrinsic mechanisms of resistance to micafungin

Nickels,

Gale,

Harrington

et al. 2024

Preprint

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glabratais an opportunistic pathogen that can resist common antifungals and rapidly acquire multidrug resistance. A large amount of genetic variation exists between isolates, which complicates generalizations. Portable Tn-seq methods can efficiently provide genome-wide information on strain differences and genetic mechanisms. Using theHermestransposon, the CBS138 reference strain and a commonly studied derivative termed 2001 were subjected to Tn-seq in control conditions and after exposure to varying doses of the clinical antifungal micafungin. The approach revealed large differences between these strains, including a 131 kb tandem duplication and a variety of fitness differences. Additionally, both strains exhibited up to 1000-fold increased transposon accessibility in subtelomeric regions relative to the BG2 strain, indicative of open subtelomeric chromatin in these isolates and large epigenetic variation within the species. Unexpectedly, the Pdr1 transcription factor conferred resistance to micafungin through targets other thanCDR1. Other micafungin resistance pathways were also revealed including mannosyltransferase activity and biosynthesis of the lipid precursor sphingosine, the drugging of which by SDZ 90-215 or myriocin enhanced the potency of micafunginin vitro. These findings provide insights into complexity of theC. glabrataspecies as well as strategies for improving antifungal efficacy.

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Section: Discussionmentioning

confidence: 95%

Tn-seq of theCandida glabratareference strain CBS138 reveals epigenetic plasticity, structural variation, and intrinsic mechanisms of resistance to micafungin

Nickels,

Gale,

Harrington

et al. 2024

Preprint

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“…An Aur1/Ipt1-like inositol-phosphotransferase and malic enzyme carried variants between the strains. Both genes participate in lipid biosynthesis, with the former governing antifungal compounds’ susceptibility (Prasad et al 2005 ; Massengo-Tiassé and Cronan 2009 ; Shahi et al 2022 ). The presence of these variants suggests that an evolutionary pressure is exerted on these genes, and that changes in their functionality may occur in an intra-species context.…”

Section: Resultsmentioning

confidence: 99%

The genomes of Scedosporium between environmental challenges and opportunism

Venice,

Spina,

Davolos

et al. 2023

IMA Fungus

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Emerging fungal pathogens are a global challenge for humankind. Many efforts have been made to understand the mechanisms underlying pathogenicity in bacteria, and OMICs techniques are largely responsible for those advancements. By contrast, our limited understanding of opportunism and antifungal resistance is preventing us from identifying, limiting and interpreting the emergence of fungal pathogens. The genus Scedosporium (Microascaceae) includes fungi with high tolerance to environmental pollution, whilst some species can be considered major human pathogens, such as Scedosporium apiospermum and Scedosporium boydii. However, unlike other fungal pathogens, little is known about the genome evolution of these organisms. We sequenced two novel genomes of Scedosporium aurantiacum and Scedosporium minutisporum isolated from extreme, strongly anthropized environments. We compared all the available Scedosporium and Microascaceae genomes, that we systematically annotated and characterized ex novo in most cases. The genomes in this family were integrated in a Phylum-level comparison to infer the presence of putative, shared genomic traits in filamentous ascomycetes with pathogenic potential. The analysis included the genomes of 100 environmental and clinical fungi, revealing poor evolutionary convergence of putative pathogenicity traits. By contrast, several features in Microascaceae and Scedosporium were detected that might have a dual role in responding to environmental challenges and allowing colonization of the human body, including chitin, melanin and other cell wall related genes, proteases, glutaredoxins and magnesium transporters. We found these gene families to be impacted by expansions, orthologous transposon insertions, and point mutations. With RNA-seq, we demonstrated that most of these anciently impacted genomic features responded to the stress imposed by an antifungal compound (voriconazole) in the two environmental strains S. aurantiacum MUT6114 and S. minutisporum MUT6113. Therefore, the present genomics and transcriptomics investigation stands on the edge between stress resistance and pathogenic potential, to elucidate whether fungi were pre-adapted to infect humans. We highlight the strengths and limitations of genomics applied to opportunistic human pathogens, the multifactoriality of pathogenicity and resistance to drugs, and suggest a scenario where pressures other than anthropic contributed to forge filamentous human pathogens.

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