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.

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.

Recent Advances in Azole Based Scaffolds as Anticandidal Agents

2019 ◽  
Vol 16 (5) ◽  
pp. 492-501 ◽  
Author(s):  
Prabhuodeyara Math Gurubasavaraj ◽  
Jasmith Shivayya Charantimath
Keyword(s):  
Drug Delivery ◽  
Drug Resistance ◽  
Candida Albicans ◽  
Drug Interactions ◽  
Fungal Pathogens ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Fungal Virulence ◽  
Compromised Patients

Aim:The present review aims to explore the development of novel antifungal agents, such as pharmacology, pharmacokinetics, spectrum of activity, safety, toxicity and other aspects that involve drug-drug interactions of the azole antifungal agents.Introduction:Fungal infections in critically ill and immune-compromised patients are increasing at alarming rates, caused mainly by Candida albicans an opportunistic fungus. Despite antifungal annihilators like amphotericin B, azoles and caspofungin, these infections are enormously increasing. The unconventional increase in such patients is a challenging task for the management of antifungal infections especially Candidiasis. Moreover, problem of toxicity associated with antifungal drugs on hosts and rise of drug-resistance in primary and opportunistic fungal pathogens has obstructed the success of antifungal therapy.Conclusion:Hence, to conflict these problems new antifungal agents with advanced efficacy, new formulations of drug delivery and novel compounds which can interact with fungal virulence are developed and used to treat antifungal infections.

scholarly journals CaNdt80 Is Involved in Drug Resistance in Candida albicans by Regulating CDR1

2004 ◽  
Vol 48 (12) ◽  
pp. 4505-4512 ◽  
Author(s):  
Chia-Geun Chen ◽  
Yun-Liang Yang ◽  
Hsin-I Shih ◽  
Chia-Li Su ◽  
Hsiu-Jung Lo
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Resistance ◽  
Candida Albicans ◽  
Type Strain ◽  
Antifungal Agents ◽  
Wild Type Strain ◽  
Efflux Pump ◽  
Antifungal Drugs ◽  
Galactosidase Activity ◽  
Wild Type

ABSTRACT Overexpression of CDR1, an efflux pump, is one of the major mechanisms contributing to drug resistance in Candida albicans. CDR1 p-lacZ was constructed and transformed into a Saccharomyces cerevisiae strain so that the lacZ gene could be used as the reporter to monitor the activity of the CDR1 promoter. Overexpression of CaNDT80, the C. albicans homolog of S. cerevisiae NDT80, increases the β-galactosidase activity of the CDR1 p-lacZ construct in S. cerevisiae. Furthermore, mutations in CaNDT80 abolish the induction of CDR1 expression by antifungal agents in C. albicans. Consistently, the Candt80/Candt80 mutant is also more susceptible to antifungal drugs than the wild-type strain. Thus, the gene for CaNdt80 may be the first gene among the regulatory factors involved in drug resistance in C. albicans whose function has been identified.

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

scholarly journals Design, synthesis and biological evaluation of novel fungicides for the management of Fusarium DieBack disease

2019 ◽  
Vol 62 (3) ◽  
Author(s):  
Israel Bonilla Landa ◽  
Osvaldo León De la Cruz ◽  
Diana Sánchez Rangel ◽  
Randy Ortiz Castro ◽  
Benjamin Rodriguez Haas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antifungal Activity ◽  
Fusarium Solani ◽  
Antifungal Agents ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Dieback Disease ◽  
Synthetic Chemist ◽  
Fusarium Dieback ◽  
Synthesis And Biological Evaluation

Abstract. Fusarium Dieback, a new and lethal insect-vectored disease can host over 300 tree species including the avocado trees. This problem has recently attracted the attention of synthetic chemist not only to develop new triazol antifungal agents but also due to severe drug resistance to “classic” triazol antifungal agents. Here, a series of novel antifungal triazoles with a p-trifluoromethylphenyl moiety were synthesized and characterized by spectroscopic and spectrometric methods. Most of the target compounds synthesized showed from modest to good inhibitory activity and less phytotoxicity in comparison with the commercially available propiconazol; in particular, compounds 7 and 13 were active against both Fusarium solani and Fusarium euwallaceae. The results showed that compounds 7, 13, and 4 have great potential to be developed as new antifungal agents because of both good antifungal activity and low phytotoxicity. SAR showed that free alcohols and not O-protected compounds significantly influence the activity. Hence, a-methyl-a-1,2,4-triazole emerged as novel compound to develop new ketone-triazole-type antifungal agents for the management of Fusarium Dieback disease Resumen. Fusarium Dieback es una nueva enfermedad letal transmitida por insectos que actúan como vectores y puede atacar a más de 300 especies de árboles, incluidos los árboles de aguacate. Recientemente, este problema ha atraído la atención de los químicos sintéticos para desarrollar nuevos agentes antifúngicos triazólicos debido a la resistencia severa que desarrollan los insectos a los agentes antifúngicos triazólicos "clásicos". Durante este trabajo, se sintetizaron nuevos triazoles antifúngicos que contienen un grupo p-trifluorometilfenilo y se caracterizaron por métodos espectroscópicos y espectrométricos. La mayoría de los compuestos diana sintetizados mostraron una actividad inhibidora de modesta a buena y menos fitotoxicidad en comparación con el propiconazol que es comercialmente disponible; en particular, los compuestos 7 y 13 mostraron ser activos contra Fusarium solani y Fusarium euwallaceae. Los resultados mostraron que los compuestos 7, 13 y 4 tienen un gran potencial para desarrollarse como nuevos agentes antifúngicos debido a la buena actividad antifúngica y su baja fitotoxicidad. SAR mostró que los alcoholes libres y no los compuestos O-protegidos influyen significativamente en la actividad. Por lo tanto, el α-metil-α-1,2,4-triazol surgió como un nuevo compuesto líder para desarrollar nuevos agentes antifúngicos tipo cetona-triazol para el tratamiento de la enfermedad Fusarium Dieback.

scholarly journals Candida albicans Sterol C-14 Reductase, Encoded by the ERG24 Gene, as a Potential Antifungal Target Site

2002 ◽  
Vol 46 (4) ◽  
pp. 947-957 ◽  
Author(s):  
N. Jia ◽  
B. Arthington-Skaggs ◽  
W. Lee ◽  
C. A. Pierson ◽  
N. D. Lees ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Fungal Pathogens ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Brefeldin A ◽  
Agricultural Applications ◽  
Mouse Model System ◽  
Cellular Inhibitors ◽  
Germ Tubes ◽  
Doubling Times

ABSTRACT The incidence of fungal infections has increased dramatically, which has necessitated additional and prolonged use of the available antifungal agents. Increased resistance to the commonly used antifungal agents, primarily the azoles, has been reported, thus necessitating the discovery and development of compounds that would be effective against the major human fungal pathogens. The sterol biosynthetic pathway has proved to be a fertile area for antifungal development, and steps which might provide good targets for novel antifungal development remain. The sterol C-14 reductase, encoded by the ERG24 gene, could be an effective target for drug development since the morpholine antifungals, inhibitors of Erg24p, have been successful in agricultural applications. The ERG24 gene of Candida albicans has been isolated by complementation of a Saccharomyces cerevisiae erg24 mutant. Both copies of the C. albicans ERG24 gene have been disrupted by using short homologous regions of the ERG24 gene flanking a selectable marker. Unlike S. cerevisiae, the C. albicans ERG24 gene was not required for growth, but erg24 mutants showed several altered phenotypes. They were demonstrated to be slowly growing, with doubling times at least twice that of the wild type. They were also shown to be significantly more sensitive to an allylamine antifungal and to selected cellular inhibitors including cycloheximide, cerulenin, fluphenazine, and brefeldin A. The erg24 mutants were also slightly resistant to the azoles. Most importantly, erg24 mutants were shown to be significantly less pathogenic in a mouse model system and failed to produce germ tubes upon incubation in human serum. On the basis of these characteristics, inhibitors of Erg24p would be effective against C. albicans.

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 High Efficiency Drug Repurposing Design for New Antifungal Agents

2019 ◽  
Vol 2 (2) ◽  
pp. 31 ◽  
Author(s):  
Jong H. Kim ◽  
Kathleen L. Chan ◽  
Luisa W. Cheng ◽  
Lisa A. Tell ◽  
Barbara A. Byrne ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Fungal Pathogens ◽  
Antifungal Agents ◽  
High Efficiency ◽  
Intervention Strategy ◽  
Drug Repurposing ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Alternative Intervention ◽  
Combined Application

Current antifungal interventions have often limited efficiency in treating fungal pathogens, particularly those resistant to commercial drugs or fungicides. Antifungal drug repurposing is an alternative intervention strategy, whereby new utility of various marketed, non-antifungal drugs could be repositioned as novel antifungal agents. In this study, we investigated “chemosensitization” as a method to improve the efficiency of antifungal drug repurposing, wherein combined application of a second compound (viz., chemosensitizer) with a conventional, non-antifungal drug could greatly enhance the antifungal activity of the co-applied drug. Redox-active natural compounds or structural derivatives, such as thymol (2-isopropyl-5-methylphenol), 4-isopropyl-3-methylphenol, or 3,5-dimethoxybenzaldehyde, could serve as potent chemosensitizers to enhance antifungal activity of the repurposed drug bithionol. Of note, inclusion of fungal mutants, such as antioxidant mutants, could also facilitate drug repurposing efficiency, which is reflected in the enhancement of antifungal efficacy of bithionol. Bithionol overcame antifungal (viz., fludioxonil) tolerance of the antioxidant mutants of the human/animal pathogen Aspergillus fumigatus. Altogether, our strategy can lead to the development of a high efficiency drug repurposing design, which enhances the susceptibility of pathogens to drugs, reduces time and costs for new antifungal development, and abates drug or fungicide resistance.

scholarly journals Current and Emerging Azole Antifungal Agents

1999 ◽  
Vol 12 (1) ◽  
pp. 40-79 ◽  
Author(s):  
Daniel J. Sheehan ◽  
Christopher A. Hitchcock ◽  
Carol M. Sibley
Keyword(s):  
Fungal Pathogens ◽  
Antifungal Agents ◽  
Susceptibility Testing ◽  
Fungal Infections ◽  
Mechanisms Of Action ◽  
Current Status ◽  
In Vitro Susceptibility ◽  
Clinical Resistance ◽  
In Vitro Susceptibility Testing

SUMMARY Major developments in research into the azole class of antifungal agents during the 1990s have provided expanded options for the treatment of many opportunistic and endemic fungal infections. Fluconazole and itraconazole have proved to be safer than both amphotericin B and ketoconazole. Despite these advances, serious fungal infections remain difficult to treat, and resistance to the available drugs is emerging. This review describes present and future uses of the currently available azole antifungal agents in the treatment of systemic and superficial fungal infections and provides a brief overview of the current status of in vitro susceptibility testing and the growing problem of clinical resistance to the azoles. Use of the currently available azoles in combination with other antifungal agents with different mechanisms of action is likely to provide enhanced efficacy. Detailed information on some of the second-generation triazoles being developed to provide extended coverage of opportunistic, endemic, and emerging fungal pathogens, as well as those in which resistance to older agents is becoming problematic, is provided.

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