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 Beauvericin Potentiates Azole Activity via Inhibition of Multidrug Efflux, BlocksC. albicansMorphogenesis, and is Effluxed via Yor1 and Circuitry Controlled by Zcf29

2016 ◽  
pp. AAC.01959-16 ◽  
Author(s):  
Tanvi Shekhar-Guturja ◽  
Walters Aji Tebung ◽  
Harley Mount ◽  
Ningning Liu ◽  
Julia R. Köhler ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Transcription Factor ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Transcriptional Profiling ◽  
Antifungal Drugs ◽  
Multidrug Efflux ◽  
Tor Signaling ◽  
Transcription Factor Genes ◽  
Life Threatening

Invasive fungal infections are a leading cause of human mortality. Effective treatment is hindered by the rapid emergence of resistance to the limited number of antifungal drugs, demanding new strategies to treat life-threatening fungal infections. Here, we explore a powerful strategy to enhance antifungal efficacy using the natural product beauvericin against leading human fungal pathogens. We found that beauvericin potentiates the activity of azole antifungals against azole-resistantCandidaisolates via inhibition of multidrug efflux, and that beauvericin itself is effluxed via Yor1. As observed inSaccharomyces cerevisiae, we determined that beauvericin inhibits TOR signaling inCandida albicans. To further characterize beauvericin activity inC. albicans, we leveraged genome sequencing of beauvericin-resistant mutants. Resistance was conferred by mutations in transcription factor genesTAC1,which is a key regulator of multidrug efflux, andZCF29, which was uncharacterized. Transcriptional profiling and chromatin immunoprecipitation coupled to microarray analyses revealed that Zcf29 binds to and regulates the expression of multidrug transporter genes. Beyond drug resistance, we also discovered that beauvericin blocks theC. albicansmorphogenetic transition from yeast to filamentous growth in response to diverse cues. We found that beauvericin represses the expression of many filament-specific genes, including the transcription factorBRG1. Thus, we illuminate novel circuitry regulating multidrug efflux, and establish that simultaneously targeting drug resistance and morphogenesis provides a promising strategy to combat life-threatening fungal infections.

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 Carrier-Mediated Drug Uptake in Fungal Pathogens

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1324
Author(s):  
Mónica Galocha ◽  
Inês Vieira Costa ◽  
Miguel Cacho Teixeira
Keyword(s):  
Drug Resistance ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Current Knowledge ◽  
Pathogenic Fungi ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
Major Facilitator Superfamily ◽  
Drug Uptake ◽  
Human Pathogens

Candida, Aspergillus, and Cryptococcus species are the most frequent cause of severe human fungal infections. Clinically relevant antifungal drugs are scarce, and their effectiveness are hampered by the ability of fungal cells to develop drug resistance mechanisms. Drug effectiveness and drug resistance in human pathogens is very often affected by their “transportome”. Many studies have covered a panoply of drug resistance mechanisms that depend on drug efflux pumps belonging to the ATP-Binding Cassette and Major Facilitator Superfamily. However, the study of drug uptake mechanisms has been, to some extent, overlooked in pathogenic fungi. This review focuses on discussing current knowledge on drug uptake systems in fungal pathogens, highlighting the need for further studies on this topic of great importance. The following subjects are covered: (i) drugs imported by known transporter(s) in pathogenic fungi; and (ii) drugs imported by known transporter(s) in the model yeast Saccharomyces cerevisiae or in human parasites, aimed at the identification of their homologs in pathogenic fungi. Besides its contribution to increase the understanding of drug-pathogen interactions, the practical implications of identifying drug importers in human pathogens are discussed, particularly focusing on drug development strategies.

scholarly journals Antifungal Innate Immunity: A Perspective from the Last 10 Years

2018 ◽  
Vol 10 (5-6) ◽  
pp. 373-397 ◽  
Author(s):  
Fabián Salazar ◽  
Gordon D. Brown
Keyword(s):  
Drug Resistance ◽  
Innate Immunity ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Antifungal Drug ◽  
Cellular Basis ◽  
Antifungal Drug Resistance ◽  
Life Threatening ◽  
Antifungal Immunity ◽  
New Strategies

Fungal pathogens can rarely cause diseases in immunocompetent individuals. However, commensal and normally nonpathogenic environmental fungi can cause life-threatening infections in immunocompromised individuals. Over the last few decades, there has been a huge increase in the incidence of invasive opportunistic fungal infections along with a worrying increase in antifungal drug resistance. As a consequence, research focused on understanding the molecular and cellular basis of antifungal immunity has expanded tremendously in the last few years. This review will provide an overview of the most exciting recent advances in innate antifungal immunity, discoveries that are helping to pave the way for the development of new strategies that are desperately needed to combat these devastating diseases.

scholarly journals Linking Cellular Morphogenesis with Antifungal Treatment and Susceptibility in Candida Pathogens

2019 ◽  
Vol 5 (1) ◽  
pp. 17 ◽  
Author(s):  
Jehoshua Sharma ◽  
Sierra Rosiana ◽  
Iqra Razzaq ◽  
Rebecca Shapiro
Keyword(s):  
Drug Resistance ◽  
Candida Species ◽  
Cellular Response ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Health Concern ◽  
Biofilm Growth ◽  
Antifungal Drug Resistance

Fungal infections are a growing public health concern, and an increasingly important cause of human mortality, with Candida species being amongst the most frequently encountered of these opportunistic fungal pathogens. Several Candida species are polymorphic, and able to transition between distinct morphological states, including yeast, hyphal, and pseudohyphal forms. While not all Candida pathogens are polymorphic, the ability to undergo morphogenesis is linked with the virulence of many of these pathogens. There are also many connections between Candida morphogenesis and antifungal drug treatment and susceptibility. Here, we review how Candida morphogenesis—a key virulence trait—is linked with antifungal drugs and antifungal drug resistance. We highlight how antifungal therapeutics are able to modulate morphogenesis in both sensitive and drug-resistant Candida strains, the shared signaling pathways that mediate both morphogenesis and the cellular response to antifungal drugs and drug resistance, and the connection between Candida morphology, drug resistance, and biofilm growth. We further review the development of anti-virulence drugs, and targeting Candida morphogenesis as a novel therapeutic strategy to target fungal pathogens. Together, this review highlights important connections between fungal morphogenesis, virulence, and susceptibility to antifungals.

scholarly journals Reinforcing the Immunocompromised Host Defense against Fungi: Progress beyond the Current State of the Art

2021 ◽  
Vol 7 (6) ◽  
pp. 451
Author(s):  
Georgios Karavalakis ◽  
Evangelia Yannaki ◽  
Anastasia Papadopoulou
Keyword(s):  
Host Defense ◽  
Hematopoietic Cell Transplantation ◽  
State Of The Art ◽  
Fungal Infections ◽  
Solid Organ Transplantation ◽  
Immunocompromised Host ◽  
Antifungal Drugs ◽  
Solid Organ ◽  
Cell Immunotherapy ◽  
Life Threatening

Despite the availability of a variety of antifungal drugs, opportunistic fungal infections still remain life-threatening for immunocompromised patients, such as those undergoing allogeneic hematopoietic cell transplantation or solid organ transplantation. Suboptimal efficacy, toxicity, development of resistant variants and recurrent episodes are limitations associated with current antifungal drug therapy. Adjunctive immunotherapies reinforcing the host defense against fungi and aiding in clearance of opportunistic pathogens are continuously gaining ground in this battle. Here, we review alternative approaches for the management of fungal infections going beyond the state of the art and placing an emphasis on fungus-specific T cell immunotherapy. Harnessing the power of T cells in the form of adoptive immunotherapy represents the strenuous protagonist of the current immunotherapeutic approaches towards combating invasive fungal infections. The progress that has been made over the last years in this field and remaining challenges as well, will be discussed.

scholarly journals The importance of rapid diagnosis for multidrug-resistant Candida: an interview with Maurizio Sanguinetti

2019 ◽  
Vol 14 (12) ◽  
pp. 1011-1012
Author(s):  
Maurizio Sanguinetti
Keyword(s):  
Infectious Diseases ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Resistance Mechanisms ◽  
Rapid Diagnosis ◽  
Antifungal Drugs ◽  
Full Professor ◽  
Research Activity ◽  
Diagnostic Strategies ◽  
Personalized Care

In this exclusive interview, Maurizio Sanguinetti discusses current issues with Candida fungal infection diagnoses, in light of its rising resistance to antifungal drugs. This interview was conducted by Ellen Colvin, Editor of Future Microbiology. Maurizio Sanguinetti, MD, is full Professor of Microbiology at the Università Cattolica del Sacro Cuore of Rome, Italy, and Director of the Institute of Microbiology and Chief of the Department of Laboratory Sciences and Infectious Diseases Sciences at the Fondazione Policlinico Agostino Gemelli IRCCS of Rome, Italy. For several years, the research activity of Maurizio Sanguinetti has mainly focused on the development of molecular methods for the rapid diagnosis of bacterial, mycobacterial and fungal infections; the elucidation of virulence and antimicrobial resistance mechanisms in clinically relevant bacterial and fungal pathogens; the characterization of the human microbiota in relationship to infectious and noninfectious diseases and implementation of new diagnostic strategies for the personalized care of patients with infectious diseases.

Resistance to antifungal therapies

2017 ◽  
Vol 61 (1) ◽  
pp. 157-166 ◽  
Author(s):  
Rajendra Prasad ◽  
Atanu Banerjee ◽  
Abdul Haseeb Shah
Keyword(s):  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Therapeutic Strategies ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
Therapeutic Interventions ◽  
Medical Professionals ◽  
Comprehensive Understanding ◽  
Novel Targets

The evolution of antifungal resistance among fungal pathogens has rendered the limited arsenal of antifungal drugs futile. Considering the recent rise in the number of nosocomial fungal infections in immunocompromised patients, the emerging clinical multidrug resistance (MDR) has become a matter of grave concern for medical professionals. Despite advances in therapeutic interventions, it has not yet been possible to devise convincing strategies to combat antifungal resistance. Comprehensive understanding of the molecular mechanisms of antifungal resistance is essential for identification of novel targets that do not promote or delay emergence of drug resistance. The present study discusses features and limitations of the currently available antifungals, mechanisms of antifungal resistance and highlights the emerging therapeutic strategies that could be deployed to combat MDR.

scholarly journals CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Claudia Spampinato ◽  
Darío Leonardi
Keyword(s):  
Antifungal Agents ◽  
Fungal Infections ◽  
Current Knowledge ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
Diagnostic Methods ◽  
Opportunistic Pathogens ◽  
Yeast Infection ◽  
Life Threatening ◽  
Therapeutic Alternatives

The genusCandidaincludes about 200 different species, but only a few species are human opportunistic pathogens and cause infections when the host becomes debilitated or immunocompromised.Candidainfections can be superficial or invasive. Superficial infections often affect the skin or mucous membranes and can be treated successfully with topical antifungal drugs. However, invasive fungal infections are often life-threatening, probably due to inefficient diagnostic methods and inappropriate initial antifungal therapies. Here, we briefly review our current knowledge of pathogenic species of the genusCandidaand yeast infection causes and then focus on current antifungal drugs and resistance mechanisms. An overview of new therapeutic alternatives for the treatment ofCandidainfections is also provided.

scholarly journals Fungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond

2021 ◽  
Vol 17 (12) ◽  
pp. e1010073
Author(s):  
Rafael W. Bastos ◽  
Luana Rossato ◽  
Gustavo H. Goldman ◽  
Daniel A. Santos
Keyword(s):  
Fungal Pathogens ◽  
Fungal Infections ◽  
Resistance Mechanism ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Cross Resistance ◽  
Term Therapy ◽  
Prior History ◽  
Plant Materials

Fungal infections are underestimated threats that affect over 1 billion people, and Candida spp., Cryptococcus spp., and Aspergillus spp. are the 3 most fatal fungi. The treatment of these infections is performed with a limited arsenal of antifungal drugs, and the class of the azoles is the most used. Although these drugs present low toxicity for the host, there is an emergence of therapeutic failure due to azole resistance. Drug resistance normally develops in patients undergoing azole long-term therapy, when the fungus in contact with the drug can adapt and survive. Conversely, several reports have been showing that resistant isolates are also recovered from patients with no prior history of azole therapy, suggesting that other routes might be driving antifungal resistance. Intriguingly, antifungal resistance also happens in the environment since resistant strains have been isolated from plant materials, soil, decomposing matter, and compost, where important human fungal pathogens live. As the resistant fungi can be isolated from the environment, in places where agrochemicals are extensively used in agriculture and wood industry, the hypothesis that fungicides could be driving and selecting resistance mechanism in nature, before the contact of the fungus with the host, has gained more attention. The effects of fungicide exposure on fungal resistance have been extensively studied in Aspergillus fumigatus and less investigated in other human fungal pathogens. Here, we discuss not only classic and recent studies showing that environmental azole exposure selects cross-resistance to medical azoles in A. fumigatus, but also how this phenomenon affects Candida and Cryptococcus, other 2 important human fungal pathogens found in the environment. We also examine data showing that fungicide exposure can select relevant changes in the morphophysiology and virulence of those pathogens, suggesting that its effect goes beyond the cross-resistance.

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