In the Crossroad Between Drug Resistance and Virulence in Fungal Pathogens

2018 ◽  
pp. 223-259
Author(s):  
Mafalda Cavalheiro ◽  
Miguel Cacho Teixeira
Keyword(s):  
Drug Resistance ◽  
Fungal Pathogens

Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence

Genetics ◽  
2021 ◽  
Author(s):  
Ci Fu ◽  
Sarah R Beattie ◽  
Andrew J Jezewski ◽  
Nicole Robbins ◽  
Luke Whitesell ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cryptococcus Neoformans ◽  
Molecular Chaperone ◽  
Fungal Pathogens ◽  
Genetic Characterization ◽  
Great Promise ◽  
Report Generation ◽  
Conditional Expression ◽  
Expression Strain

Abstract The opportunistic human fungal pathogen Cryptococcus neoformans has tremendous impact on global health, causing 181,000 deaths annually. Current treatment options are limited, and the frequent development of drug resistance exacerbates the challenge of managing invasive cryptococcal infections. In diverse fungal pathogens, the essential molecular chaperone Hsp90 governs fungal survival, drug resistance, and virulence. Therefore, targeting this chaperone has emerged as a promising approach to combat fungal infections. However, the role of Hsp90 in supporting C. neoformans pathogenesis remains largely elusive due to a lack of genetic characterization. To help dissect the functions of Hsp90 in C. neoformans, we generated a conditional expression strain in which HSP90 is under control of the copper-repressible promoter CTR4-2. Addition of copper to culture medium depleted Hsp90 transcript and protein levels in this strain, resulting in compromised fungal growth at host temperature; increased sensitivity to stressors, including the azole class of antifungals; altered C. neoformans morphology; and impaired melanin production. Finally, leveraging the fact that copper concentrations vary widely in different mouse tissues, we demonstrated attenuated virulence for the CTR4-2p-HSP90 mutant specifically in an inhalation model of Cryptococcus infection. During invasion and establishment of infection in this mouse model, the pathogen is exposed to the relatively high copper concentrations found in the lung as compared to blood. Overall, this work generates a tractable genetic system to study the role of Hsp90 in supporting the pathogenicity of C. neoformans and provides proof-of-principle that targeting Hsp90 holds great promise as a strategy to control cryptococcal infection. Article Summary Hsp90 is a conserved molecular chaperone that modulates virulence traits and drug resistance in fungal pathogens. Despite the potential of Hsp90 as a target for antifungal development, genetic characterization remains lacking in Cryptococcus neoformans. Here, we report generation of a C. neoformans HSP90 conditional expression strain. Utilizing this genetic tool, we found depletion of Hsp90 impacted tolerance to environmental stresses, growth at physiological temperature, and virulence in vivo. Thus, we suggest targeting Hsp90 is a viable strategy for treating cryptococcosis.

scholarly journals Bryophytes as a safeguard of fruits from postharvest fungal diseases: A Review

2022 ◽  
Author(s):  
Supriya Joshi ◽  
Prerna Bhardwaj ◽  
Afroz Alam
Keyword(s):  
Drug Resistance ◽  
Fungal Pathogens ◽  
Fruits And Vegetables ◽  
Antifungal Agents ◽  
Green Technology ◽  
Land Plants ◽  
Protective Mechanism ◽  
Commercial Scale ◽  
Amphibious Plants ◽  
Regular Practice

Postharvest losses from fungal pathogens to essential fruits and vegetables are enormous and alarming. Orthodox synthetic fungicides are being used as a regular practice to restrict these losses. However, now by knowing the hazards of these chemical-based fungicides, the situation demands alternative green technology. Consequently, many angiosperms plant extracts have been evaluated for their antifungal nature and achieved substantial success. However, the second most prevalent flora on land, i.e. bryophytes, have been scarcely used and somewhat remain neglected besides their remarkable thallus organization, water relations and antimicrobial potential. For postharvest fungus control, these bryophytes, the first land plants' extracts to be researched and promoted due to concerns about drug resistance, nephrotoxicity and biomagnification related to current synthetic fungicides. Since these amphibious plants have their unique protective mechanism against fungal or bacterial attacks due to their unique phytochemistry, therefore have great potential to be used as eco-friendly fungicides. Considering these factors, this article seeks to direct the attention of interested researchers toward the relatively accessible but vast underutilised bryo-diversity to investigate their remarkable potential as postharvest antifungal agents first in laboratories and then on a commercial scale in the future.

Elucidating drug resistance in human fungal pathogens

2014 ◽  
Vol 9 (4) ◽  
pp. 523-542 ◽  
Author(s):  
Jinglin Lucy Xie ◽  
Elizabeth J Polvi ◽  
Tanvi Shekhar-Guturja ◽  
Leah E Cowen
Keyword(s):  
Drug Resistance ◽  
Fungal Pathogens

scholarly journals Prevalence and Therapeutic Challenges of Fungal Drug Resistance: Role for Plants in Drug Discovery

Antibiotics ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 150 ◽  
Author(s):  
Lewis Marquez ◽  
Cassandra L. Quave
Keyword(s):  
United States ◽  
Drug Resistance ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
The United States ◽  
Multidrug Resistant ◽  
Modern Medicine ◽  
Candida Auris ◽  
Medical Ethnobotany ◽  
Global Issue

Antimicrobial resistance is a global issue that threatens the effective practice of modern medicine and global health. The emergence of multidrug-resistant (MDR) fungal strains of Candida auris and azole-resistant Aspergillus fumigatus were highlighted in the Centers for Disease Control and Prevention’s (CDC) 2019 report, Antibiotic Resistance Threats in the United States. Conventional antifungals used to treat fungal infections are no longer as effective, leading to increased mortality. Compounding this issue, there are very few new antifungals currently in development. Plants from traditional medicine represent one possible research path to addressing the issue of MDR fungal pathogens. In this commentary piece, we discuss how medical ethnobotany—the study of how people use plants in medicine—can be used as a guide to identify plant species for the discovery and development of novel antifungal therapies.

Progress and prospects for targeting Hsp90 to treat fungal infections

Parasitology ◽  
2014 ◽  
Vol 141 (9) ◽  
pp. 1127-1137 ◽  
Author(s):  
AMANDA VERI ◽  
LEAH E. COWEN
Keyword(s):  
Drug Resistance ◽  
Anticancer Agents ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Effective Combination ◽  
New Strategy ◽  
Life Threatening ◽  
Hsp90 Chaperone ◽  
Hsp90 Function

SummaryFungal pathogens pose a major threat to human health worldwide. They infect billions of people each year, leading to at least 1·5 million deaths. Treatment of fungal infections is difficult due to the limited number of clinically useful antifungal drugs, and the emergence of drug resistance. A promising new strategy to enhance the efficacy of antifungal drugs and block the evolution of drug resistance is to target the molecular chaperone Hsp90. Pharmacological inhibitors of Hsp90 function that are in development as anticancer agents have potential to be repurposed as agents for combination antifungal therapy for some applications, such as biofilm infections. For systemic infections, however, effective combination therapy regimens may require Hsp90 inhibitors that can selectively target Hsp90 in the pathogen, or alternate strategies to compromise function of the Hsp90 chaperone machine. Selectively impairing Hsp90 function in the pathogen could in principle be achieved by targeting Hsp90 co-chaperones or regulators of Hsp90 function that are more divergent between pathogen and host than Hsp90. Antifungal combination therapies could also exploit downstream effectors of Hsp90 that are critical for fungal drug resistance and virulence. Here, we discuss the progress and prospects for establishing Hsp90 as an important therapeutic target for life-threatening fungal infections.

scholarly journals Tetraploidy accelerates adaption under drug-selection in a fungal pathogen

2021 ◽  
Author(s):  
Ognenka Avramovska ◽  
Emily Rego ◽  
Meleah A Hickman
Keyword(s):  
Drug Resistance ◽  
Genome Size ◽  
Fungal Pathogen ◽  
Fungal Pathogens ◽  
Antifungal Drug ◽  
Drug Selection ◽  
Antifungal Drug Resistance ◽  
Evolutionary Trajectories ◽  
Work Supports ◽  
Initial Genome

AbstractBaseline ploidy significantly impacts evolutionary trajectories, and in particular, tetraploidy has been associated with higher rates of adaptation compared to haploidy and diploidy. While the majority of experimental evolution studies investigating ploidy use Saccharomyces cerivisiae, the fungal pathogen Candida albicans is a powerful system to investigate ploidy dynamics, particularly in the context of antifungal drug resistance. C. albicans laboratory and clinical strains are predominantly diploid, but have also been isolated as haploid and polyploid. Here, we evolved diploid and tetraploid C. albicans for ∼60 days in the antifungal drug caspofungin. Tetraploid-evolved lines adapted faster than diploid-evolved lines and reached higher levels of caspofungin resistance. While diploid-evolved lines generally maintained their initial genome size, tetraploid-evolved lines rapidly underwent genome-size reductions and did so prior to caspofungin adaption. Furthermore, fitness costs in the absence of drug selection were significantly less in tetraploid-evolved lines compared to the diploid-evolved lines. Taken together, this work supports a model of adaptation in which the tetraploid state is transient but its ability to rapidly transition ploidy states improves adaptative outcomes and may drive drug resistance in fungal pathogens.

scholarly journals Drug-resistant epimutants exhibit organ-specific stability and induction during murine infections caused by the human fungal pathogen Mucor circinelloides

2019 ◽  
Author(s):  
Zanetta Chang ◽  
Joseph Heitman
Keyword(s):  
Drug Resistance ◽  
Murine Model ◽  
Fungal Pathogen ◽  
Fungal Pathogens ◽  
Antifungal Agents ◽  
Mucor Circinelloides ◽  
Antifungal Resistance ◽  
Morbidity And Mortality ◽  
The Brain

ABSTRACTThe environmentally ubiquitous fungus Mucor circinelloides is a primary cause of the emerging disease mucormycosis. Mucor infection is notable for causing high morbidity and mortality, especially in immunosuppressed patients, while being inherently resistant to the majority of clinically available antifungal drugs. A new, RNAi-dependent, and reversible epigenetic mechanism of antifungal resistance – epimutation - was recently discovered in M. circinelloides. However, the effects of epimutation in a host-pathogen setting were unknown. We employed a systemic, intravenous murine model of Mucor infection to elucidate the potential impact of epimutation in vivo. Infection with an epimutant strain resistant to the antifungal agents FK506 and rapamycin revealed that the epimutant-induced drug resistance was stable in vivo in a variety of different organs and tissues. Reversion of the epimutant-induced drug resistance was observed to be more rapid in isolates from the brain, as compared to those recovered from the liver, spleen, kidney, or lungs. Importantly, infection with a wild-type strain of Mucor led to increased rates of epimutation after strains were recovered from organs and exposed to FK506 stress in vitro. Once again, this effect was more pronounced in strains recovered from the brain than from other organs. In summary, we report the rapid induction and reversion of RNAi-dependent drug resistance after in vivo passage through a murine model, with pronounced impact in strains recovered from brain. Defining the role played by epimutation in drug resistance and infection advances our understanding of Mucor and other fungal pathogens, and may have implications for antifungal therapy.IMPORTANCEThe emerging fungal pathogen Mucor circinelloides causes a severe infection, mucormycosis, which leads to considerable morbidity and mortality. Treatment of Mucor infection is challenging because Mucor is inherently resistant to nearly all clinical antifungal agents. An RNAi-dependent and reversible mechanism of antifungal resistance, epimutation, was recently described in Mucor. Epimutation has not been studied in vivo and it was unclear whether it would contribute to antifungal resistance observed clinically. We demonstrate that epimutation can be both induced and reverted after in vivo passage through a mouse model; rates of both induction and reversion are higher after brain infection than after infection of other organs (liver, spleen, kidneys, or lungs). Elucidating the roles played by epimutation in drug resistance and infection will improve our understanding of Mucor and other fungal pathogens, and may have implications for antifungal treatment.

scholarly journals Drug-Resistant Epimutants Exhibit Organ-Specific Stability and Induction during Murine Infections Caused by the Human Fungal Pathogen Mucor circinelloides

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Zanetta Chang ◽  
Joseph Heitman
Keyword(s):  
Drug Resistance ◽  
Murine Model ◽  
Fungal Pathogen ◽  
Fungal Pathogens ◽  
Antifungal Agents ◽  
Mucor Circinelloides ◽  
Antifungal Resistance ◽  
Content Type ◽  
The Brain

ABSTRACT The environmentally ubiquitous fungus Mucor circinelloides is a primary cause of the emerging disease mucormycosis. Mucor infection is notable for causing high morbidity and mortality, especially in immunosuppressed patients, while being inherently resistant to the majority of clinically available antifungal drugs. A new, RNA interference (RNAi)-dependent, and reversible epigenetic mechanism of antifungal resistance—epimutation—was recently discovered in M. circinelloides. However, the effects of epimutation in a host-pathogen setting were unknown. We employed a systemic, intravenous murine model of Mucor infection to elucidate the potential impact of epimutation in vivo. Infection with an epimutant strain resistant to the antifungal agents FK506 and rapamycin revealed that the epimutant-induced drug resistance was stable in vivo in a variety of different organs and tissues. Reversion of the epimutant-induced drug resistance was observed to be more rapid in isolates from the brain than in isolates recovered from the liver, spleen, kidney, or lungs. Importantly, infection with a wild-type strain of Mucor led to increased rates of epimutation after strains were recovered from organs and exposed to FK506 stress in vitro. Once again, this effect was more pronounced in strains recovered from the brain than from other organs. In summary, we report the rapid induction and reversion of RNAi-dependent drug resistance after in vivo passage through a murine model, with pronounced impact in strains recovered from brain. Defining the role played by epimutation in drug resistance and infection advances our understanding of Mucor and other fungal pathogens and may have implications for antifungal therapy. IMPORTANCE The emerging fungal pathogen Mucor circinelloides causes a severe infection, mucormycosis, which leads to considerable morbidity and mortality. Treatment of Mucor infection is challenging because Mucor is inherently resistant to nearly all clinical antifungal agents. An RNAi-dependent and reversible mechanism of antifungal resistance, epimutation, was recently reported for Mucor. Epimutation has not been studied in vivo, and it was unclear whether it would contribute to antifungal resistance observed clinically. We demonstrate that epimutation can both be induced and reverted after in vivo passage through a mouse; rates of both induction and reversion are higher after brain infection than after infection of other organs (liver, spleen, kidneys, or lungs). Elucidating the roles played by epimutation in drug resistance and infection will improve our understanding of Mucor and other fungal pathogens and may have implications for antifungal treatment.

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