Targeting stress response pathways with alternative strategies as a novel antifungal approach

2021 ◽  
Vol 21 ◽  
Author(s):  
Sonam Ruhil ◽  
Vikash Kumar ◽  
Meenakshi Balhara ◽  
Monika Malik ◽  
Anil K. Chhillar
Keyword(s):  
Drug Resistance ◽  
Fungal Infections ◽  
Essential Gene ◽  
Fungal Growth ◽  
High Morbidity ◽  
Invasive Infection ◽  
Alternative Strategies ◽  
Antifungal Drug Resistance ◽  
Novel Approach ◽  
Stress Pathway

: Fungi are recognized as key pathogens in immunocompromised patients. The invasive infection always remains a problem for clinician due to high morbidity and mortality. The treatments of fungal infections are hampered by conventional drugs which are associated with resistance. Drug resistance has become an important problem in a variety of infectious diseases. The rise in the incidence of fungal infections and drug resistance has intensified the need for alternate therapies that affect a new target. This new target must be a growth essential gene product like stress pathway. It has been found that stress pathways can be a potential target in opportunistic fungal infection which played important role in virulence of pathogens. It was helpful in protection from host defense, normal fungal growth and antifungal drug resistance. The disruption of pathway using alternative strategies (chemosensitization and photo-dynamics therapy) can be a novel approach in fighting fungal infections and for drug design.

Antimycotic drugs and their mechanisms of resistance to Candida species

2021 ◽  
Vol 22 ◽  
Author(s):  
Sweety Dahiya ◽  
Namita Sharma ◽  
Aruna Punia ◽  
Pooja Choudhary ◽  
Prity Gulia ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Species ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Treatment Strategies ◽  
Distinct Species ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Success Rates ◽  
Antifungal Drug Resistance

: Fungal infections have shown an upsurge in recent decades, mainly because of the increasing number of immunocompromised patients, and the occurrence of invasive candidiasis is found to be 7-15 folds greater than that of invasive aspergillosis. The genus Candida comprises of more than 150 distinct species; however, only a few of them are found to be pathogenic to humans. Mortality rates of Candida species are found to be around 45%, and the reasons for this intensified mortality are inefficient diagnostic techniques and unfitting initial treatment strategies. There are only a few antifungal drug classes that are employed for the remedy of invasive fungal infections, including azoles, polyenes, echinocandins, and pyrimidine analogs. During the last 2-3 decades, the usage of antifungal drugs has increased several folds, due to which the reports of escalating antifungal drug resistance have also been recorded. The resistance is mostly to the triazole-based compounds. Due to antifungal drug resistance, the success rates of treatment have been reduced and major changes have been observed in the frequency of fungal infections. In this review, we have summarized the major molecular mechanisms for the development of antifungal drug resistance.

scholarly journals Fungal biofilm architecture produces hypoxic microenvironments that drive antifungal resistance

2020 ◽  
Vol 117 (36) ◽  
pp. 22473-22483 ◽  
Author(s):  
Caitlin H. Kowalski ◽  
Kaesi A. Morelli ◽  
Daniel Schultz ◽  
Carey D. Nadell ◽  
Robert A. Cramer
Keyword(s):  
Drug Resistance ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Drug Resistant ◽  
Antifungal Drug Resistance ◽  
Oxygen Gradients ◽  
Biofilm Architecture

Human fungal infections may fail to respond to contemporary antifungal therapies in vivo despite in vitro fungal isolate drug susceptibility. Such a discrepancy between in vitro antimicrobial susceptibility and in vivo treatment outcomes is partially explained by microbes adopting a drug-resistant biofilm mode of growth during infection. The filamentous fungal pathogenAspergillus fumigatusforms biofilms in vivo, and during biofilm growth it has reduced susceptibility to all three classes of contemporary antifungal drugs. Specific features of filamentous fungal biofilms that drive antifungal drug resistance remain largely unknown. In this study, we applied a fluorescence microscopy approach coupled with transcriptional bioreporters to define spatial and temporal oxygen gradients and single-cell metabolic activity withinA. fumigatusbiofilms. Oxygen gradients inevitably arise duringA. fumigatusbiofilm maturation and are both critical for, and the result of,A. fumigatuslate-stage biofilm architecture. We observe that these self-induced hypoxic microenvironments not only contribute to filamentous fungal biofilm maturation but also drive resistance to antifungal treatment. Decreasing oxygen levels toward the base ofA. fumigatusbiofilms increases antifungal drug resistance. Our results define a previously unknown mechanistic link between filamentous fungal biofilm physiology and contemporary antifungal drug resistance. Moreover, we demonstrate that drug resistance mediated by dynamic oxygen gradients, found in many bacterial biofilms, also extends to the fungal kingdom. The conservation of hypoxic drug-resistant niches in bacterial and fungal biofilms is thus a promising target for improving antimicrobial therapy efficacy.

scholarly journals Efflux-Mediated Antifungal Drug Resistance

2009 ◽  
Vol 22 (2) ◽  
pp. 291-321 ◽  
Author(s):  
Richard D. Cannon ◽  
Erwin Lamping ◽  
Ann R. Holmes ◽  
Kyoko Niimi ◽  
Philippe V. Baret ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Efflux Pump ◽  
Fungal Infections ◽  
Efflux Pumps ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Model Systems ◽  
Attributable Mortality ◽  
Azole Resistance ◽  
Antifungal Drug Resistance

SUMMARY Fungi cause serious infections in the immunocompromised and debilitated, and the incidence of invasive mycoses has increased significantly over the last 3 decades. Slow diagnosis and the relatively few classes of antifungal drugs result in high attributable mortality for systemic fungal infections. Azole antifungals are commonly used for fungal infections, but azole resistance can be a problem for some patient groups. High-level, clinically significant azole resistance usually involves overexpression of plasma membrane efflux pumps belonging to the ATP-binding cassette (ABC) or the major facilitator superfamily class of transporters. The heterologous expression of efflux pumps in model systems, such Saccharomyces cerevisiae, has enabled the functional analysis of efflux pumps from a variety of fungi. Phylogenetic analysis of the ABC pleiotropic drug resistance family has provided a new view of the evolution of this important class of efflux pumps. There are several ways in which the clinical significance of efflux-mediated antifungal drug resistance can be mitigated. Alternative antifungal drugs, such as the echinocandins, that are not efflux pump substrates provide one option. Potential therapeutic approaches that could overcome azole resistance include targeting efflux pump transcriptional regulators and fungal stress response pathways, blockade of energy supply, and direct inhibition of efflux pumps.

scholarly journals Clinical, Cellular, and Molecular Factors That Contribute to Antifungal Drug Resistance

1998 ◽  
Vol 11 (2) ◽  
pp. 382-402 ◽  
Author(s):  
Theodore C. White ◽  
Kieren A. Marr ◽  
Raleigh A. Bowden
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Cellular Level ◽  
Antifungal Drug ◽  
Clinical Factors ◽  
Antifungal Drug Resistance ◽  
Aids Epidemic ◽  
Immunosuppressed Patients ◽  
Target Enzyme

SUMMARY In the past decade, the frequency of diagnosed fungal infections has risen sharply due to several factors, including the increase in the number of immunosuppressed patients resulting from the AIDS epidemic and treatments during and after organ and bone marrow transplants. Linked with the increase in fungal infections is a recent increase in the frequency with which these infections are recalcitrant to standard antifungal therapy. This review summarizes the factors that contribute to antifungal drug resistance on three levels: (i) clinical factors that result in the inability to successfully treat refractory disease; (ii) cellular factors associated with a resistant fungal strain; and (iii) molecular factors that are ultimately responsible for the resistance phenotype in the cell. Many of the clinical factors that contribute to resistance are associated with the immune status of the patient, with the pharmacology of the drugs, or with the degree or type of fungal infection present. At a cellular level, antifungal drug resistance can be the result of replacement of a susceptible strain with a more resistant strain or species or the alteration of an endogenous strain (by mutation or gene expression) to a resistant phenotype. The molecular mechanisms of resistance that have been identified to date in Candida albicans include overexpression of two types of efflux pumps, overexpression or mutation of the target enzyme, and alteration of other enzymes in the same biosynthetic pathway as the target enzyme. Since the study of antifungal drug resistance is relatively new, other factors that may also contribute to resistance are discussed.

scholarly journals Insights into the global emergence of antifungal drug resistance

2019 ◽  
Vol 40 (2) ◽  
pp. 87
Author(s):  
Kylie Boyce ◽  
Orla Morrissey ◽  
Alexander Idnurm ◽  
Ian Macreadie
Keyword(s):  
Drug Resistance ◽  
Intensive Care ◽  
Fungal Infections ◽  
Invasive Fungal Disease ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Global Burden ◽  
Median Cost ◽  
Antifungal Drug Resistance ◽  
Drug Classes

The global prevalence of fungal diseases has escalated in the last several decades. Currently, it is estimated that fungi infect 1.7 billion people annually and result in 1.5 million deaths every year1. Deaths due to fungal infections are increasing, with mortality often exceeding 50%, further increasing to 100% if treatment is delayed1. Despite these staggering figures, the contribution of fungal infections to the global burden of disease remains under-recognised. In Australia, over a 5-year period fungal infections cost Australia an estimated $583 million2. The median cost for one invasive fungal disease (IFD) is AU$30957, increasing to AU$80291 if the patient is admitted to an intensive care unit3. Treatment of fungal infections poses significant challenges due to the small number of safe and effective antifungal drugs available and emerging antifungal drug resistance. Resistance to every class of antifungal drugs has been described and for some drug classes is extremely common4,5.

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 The discovery of biological subphenotypes in ARDS: a novel approach to targeted medicine?

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Karin Wildi ◽  
Samantha Livingstone ◽  
Chiara Palmieri ◽  
Gianluigi LiBassi ◽  
Jacky Suen ◽  
...  
Keyword(s):  
Age Groups ◽  
Geographical Location ◽  
High Morbidity ◽  
Shock State ◽  
Pharmacological Agents ◽  
New Approach ◽  
Novel Approach ◽  
Active Research ◽  
Targeted Medicine ◽  
Core Features

AbstractThe acute respiratory distress syndrome (ARDS) is a severe lung disorder with a high morbidity and mortality which affects all age groups. Despite active research with intense, ongoing attempts in developing pharmacological agents to treat ARDS, its mortality rate remains unaltered high and treatment is still only supportive. Over the years, there have been many attempts to identify meaningful subgroups likely to react differently to treatment among the heterogenous ARDS population, most of them unsuccessful. Only recently, analysis of large ARDS cohorts from randomized controlled trials have identified the presence of distinct biological subphenotypes among ARDS patients: a hypoinflammatory (or uninflamed; named P1) and a hyperinflammatory (or reactive; named P2) subphenotype have been proposed and corroborated with existing retrospective data. The hyperinflammatory subphenotyope was clearly associated with shock state, metabolic acidosis, and worse clinical outcomes. Core features of the respective subphenotypes were identified consistently in all assessed cohorts, independently of the studied population, the geographical location, the study design, or the analysis method. Additionally and clinically even more relevant treatment efficacies, as assessed retrospectively, appeared to be highly dependent on the respective subphenotype. This discovery launches a promising new approach to targeted medicine in ARDS. Even though it is now widely accepted that each ARDS subphenotype has distinct functional, biological, and mechanistic differences, there are crucial gaps in our knowledge, hindering the translation to bedside application. First of all, the underlying driving biological factors are still largely unknown, and secondly, there is currently no option for fast and easy identification of ARDS subphenotypes. This narrative review aims to summarize the evidence in biological subphenotyping in ARDS and tries to point out the current issues that will need addressing before translation of biological subohenotypes into clinical practice will be possible.

scholarly journals CD137 Signaling Is Critical in Fungal Clearance during Systemic Candida albicans Infection

2021 ◽  
Vol 7 (5) ◽  
pp. 382
Author(s):  
Vuvi G. Tran ◽  
Na N. Z. Nguyen ◽  
Byungsuk Kwon
Keyword(s):  
Candida Albicans ◽  
Defense Mechanisms ◽  
Tumor Necrosis ◽  
Fungal Infections ◽  
Fungal Growth ◽  
Wild Type ◽  
Agonistic Antibody ◽  
Innate Defense ◽  
Surface Receptor ◽  
Candida Albicans Infection

Invasive fungal infections by Candida albicans frequently cause mortality in immunocompromised patients. Neutrophils are particularly important for fungal clearance during systemic C. albican infection, yet little has been known regarding which surface receptor controls neutrophils’ antifungal activities. CD137, which is encoded by Tnfrsf9, belongs to the tumor necrosis receptor superfamily and has been shown to regulate neutrophils in Gram-positive bacterial infection. Here, we used genetic and immunological tools to probe the involvement of neutrophil CD137 signaling in innate defense mechanisms against systemic C. albicans infection. We first found that Tnfrsf9−/− mice were susceptible to C. albicans infection, whereas injection of anti-CD137 agonistic antibody protected the host from infection, suggesting that CD137 signaling is indispensable for innate immunity against C. albicans infection. Priming of isolated neutrophils with anti-CD137 antibody promoted their phagocytic and fungicidal activities through phospholipase C. In addition, injection of anti-CD137 antibody significantly augmented restriction of fungal growth in Tnfrsf9−/− mice that received wild-type (WT) neutrophils. In conclusion, our results demonstrate that CD137 signaling contributes to defense mechanisms against systemic C. albicans infection by promoting rapid fungal clearance.

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