Heteroresistance and fungi

Ferreira, Gabriella Freitas; Santos, Danielle Anjos dos

doi:10.1111/myc.12639

Cited by 20 publications

(17 citation statements)

References 50 publications

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“…It consists of the ability of a subpopulation of microorganism to adapt to high concentrations of the drug, resulting in resistant homogenous populations. However, heteroresistant strains return to the initial phenotype when the stimulus with the drug is withdrawn [78].…”

Section: Resistance In Pathogenic Yeasts: a Significant Problemmentioning

confidence: 99%

Phytochemicals and Their Antifungal Potential against Pathogenic Yeasts

Monteiro¹,

Santos²

2020

Phytochemicals in Human Health

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The rate of fungal infections is increasing rapidly, and pathogenesis of their species is poorly understood. Among fungi, Candida species are a major cause of morbidity and mortality worldwide and thus represent a serious threat to public health. In addition, Cryptococcus spp. are yeasts responsible for serious lung infections and meningitis. Polyenes, fluoropyrimidines, echinocandins, and azoles are used as commercial antifungal agents to treat fungal infections. However, the presence of intrinsic and developed resistance against azole antifungals has been extensively documented. The re-emergence of classical fungal diseases has occurred because of the increment of the antifungal resistance phenomenon. In this way, the development of new satisfactory therapy for fungal diseases persists as a major challenge of present-day medicine. The urgent need includes the development of alternative drugs that are more efficient and tolerant than those traditional already in use. The identification of new substances with potential antifungal effect at low concentrations or in combination is also a possibility. This chapter briefly examines the infections caused by Candida and Cryptococcus species and focuses on describing some of the promising alternative molecules and/or substances that could be used as antifungal agents, their mechanisms of action, and their use in combination with traditional drugs.

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Section: Resistance In Pathogenic Yeasts: a Significant Problemmentioning

confidence: 99%

Phytochemicals and Their Antifungal Potential against Pathogenic Yeasts

Monteiro¹,

Santos²

2020

Phytochemicals in Human Health

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“…Even though an Aspergillus colony originates from one conidium with a single nucleus, heterogeneity in the physiological activities in different regions of a colony or in different hyphal compartments within a single hyphae has been repeatedly noticed [7]. This heterogeneity is also observed for a conidial population and linked to resistance to antifungal drugs [8]. Bleichroldt et al [9] identified distinct subpopulations of A. fumigatus conidia showing different patterns of heterogeneity at the cell wall level that manifest differential fitness to the antifungal caspofungin.…”

Section: Introductionmentioning

confidence: 99%

Aspergillus fumigatus, One Uninucleate Species with Disparate Offspring

Danion

Rhijn

Dufour

et al. 2021

JoF

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Establishment of a fungal infection due to Aspergillus fumigatus relies on the efficient germination of the airborne conidia once they penetrate the respiratory tract. However, the features of conidial germination have been poorly explored and understood in this fungal species as well as in other species of filamentous fungi. We show here that the germination of A. fumigatus is asynchronous. If the nutritional environment and extensive gene deletions can modify the germination parameters for A. fumigatus, the asynchrony is maintained in all germinative conditions tested. Even though the causes for this asynchrony of conidial germination remain unknown, asynchrony is essential for the completion of the biological cycle of this filamentous fungus.

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“…Heteroresistance to antifungal drugs is a recognized yet poorly understood subpopulation phenomenon observed in pathogenic fungi under drug pressure (14). As with bacteria such as Staphylococcus aureus (15) and Mycobacterium tuberculosis (16), studies of heteroresistance in fungi have been hampered by a lack of consistency in methodology and definitions (17, 18). Heteroresistance to FLC has been detected in clinical strains of Candida glabrata, although the mechanisms and clinical impact of this remain unknown (19).…”

Section: Introductionmentioning

confidence: 99%

Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis

Stone

Rhodes

Fisher

et al. 2019

Journal of Clinical Investigation

134

142

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BACKGROUND. Cryptococcal meningitis (CM) causes an estimated 180,000 deaths annually, predominantly in sub-Saharan Africa, where most patients receive fluconazole (FLC) monotherapy. While relapse after FLC monotherapy with resistant strains is frequently observed, the mechanisms and impact of emergence of FLC resistance in human CM are poorly understood. Heteroresistance (HetR) — a resistant subpopulation within a susceptible strain — is a recently described phenomenon in Cryptococcus neoformans ( Cn ) and Cryptococcus gattii ( Cg ), the significance of which has not previously been studied in humans. METHODS. A cohort of 20 patients with HIV-associated CM in Tanzania was prospectively observed during therapy with either FLC monotherapy or in combination with flucytosine (5FC). Total and resistant subpopulations of Cryptococcus spp . were quantified directly from patient cerebrospinal fluid (CSF). Stored isolates underwent whole genome sequencing and phenotypic characterization. RESULTS. Heteroresistance was detectable in Cryptococcus spp . in the CSF of all patients at baseline (i.e., prior to initiation of therapy). During FLC monotherapy, the proportion of resistant colonies in the CSF increased during the first 2 weeks of treatment. In contrast, no resistant subpopulation was detectable in CSF by day 14 in those receiving a combination of FLC and 5FC. Genomic analysis revealed high rates of aneuploidy in heteroresistant colonies as well as in relapse isolates, with chromosome 1 (Chr1) disomy predominating. This is apparently due to the presence on Chr1 of ERG11 , which is the FLC drug target, and AFR1, which encodes a drug efflux pump. In vitro efflux levels positively correlated with the level of heteroresistance. CONCLUSION. Our findings demonstrate for what we believe is the first time the presence and emergence of aneuploidy-driven FLC heteroresistance in human CM, association of efflux levels with heteroresistance, and the successful suppression of heteroresistance with 5FC/FLC combination therapy. FUNDING. This work was supported by the Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z and the Daniel Turnberg Travel Fellowship.

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Heteroresistance and fungi

Cited by 20 publications

References 50 publications

Phytochemicals and Their Antifungal Potential against Pathogenic Yeasts

Phytochemicals and Their Antifungal Potential against Pathogenic Yeasts

Aspergillus fumigatus, One Uninucleate Species with Disparate Offspring

Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis

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