scholarly journals Marine-Derived Compounds and Prospects for Their Antifungal Application

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5856
Author(s):  
Joana Cardoso ◽  
Darlan Gonçalves Nakayama ◽  
Emília Sousa ◽  
Eugénia Pinto
Keyword(s):  
Biofilm Formation ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Mechanisms Of Action ◽  
Antifungal Compounds ◽  
Recent Developments ◽  
Marine Products ◽  
New Strategies

The introduction of antifungals in clinical practice has an enormous impact on the provision of medical care, increasing the expectancy and quality of life mainly of immunocompromised patients. However, the emergence of pathogenic fungi that are resistant and multi-resistant to the existing antifungal therapy has culminated in fungal infections that are almost impossible to treat. Therefore, there is an urgent need to discover new strategies. The marine environment has proven to be a promising rich resource for the discovery and development of new antifungal compounds. Thus, this review summarizes more than one hundred marine natural products, or their derivatives, which are categorized according to their sources—sponges, bacteria, fungi, and sea cucumbers—as potential candidates as antifungal agents. In addition, this review focus on recent developments using marine antifungal compounds as new and effective approaches for the treatment of infections caused by resistant and multi-resistant pathogenic fungi and/or biofilm formation; other perspectives on antifungal marine products highlight new mechanisms of action, the combination of antifungal and non-antifungal agents, and the use of nanoparticles and anti-virulence therapy.

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.

Antibiofilm activity of antifungal drugs, including the novel drug olorofim, against Lomentospora prolificans

2020 ◽  
Author(s):  
Lisa Kirchhoff ◽  
Silke Dittmer ◽  
Ann-Kathrin Weisner ◽  
Jan Buer ◽  
Peter-Michael Rath ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Biofilm Formation ◽  
Laser Scanning ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Pathogenic Fungus ◽  
Antifungal Drugs ◽  
Laser Scanning Microscopy ◽  
Confocal Laser ◽  
Antibiofilm Activity

Abstract Objectives Patients with immunodeficiency or cystic fibrosis frequently suffer from respiratory fungal infections. In particular, biofilm-associated fungi cause refractory infection manifestations, linked to increased resistance to anti-infective agents. One emerging filamentous fungus is Lomentospora prolificans. Here, the biofilm-formation capabilities of L. prolificans isolates were investigated and the susceptibility of biofilms to various antifungal agents was analysed. Methods Biofilm formation of L. prolificans (n = 11) was estimated by crystal violet stain and antibiofilm activity was additionally determined via detection of metabolically active biofilm using an XTT assay. Amphotericin B, micafungin, voriconazole and olorofim were compared with regard to their antibiofilm effects when added prior to adhesion, after adhesion and on mature and preformed fungal biofilms. Imaging via confocal laser scanning microscopy was carried out to demonstrate the effect of drug treatment on the fungal biofilm. Results Antibiofilm activities of the tested antifungal agents were shown to be most effective on adherent cells whilst mature biofilm was the most resistant. The most promising antibiofilm effects were detected with voriconazole and olorofim. Olorofim showed an average minimum biofilm eradication concentration (MBEC) of 0.06 mg/L, when added prior to and after adhesion. The MBECs of voriconazole were ≤4 mg/L. On mature biofilm the MBECs of olorofim and voriconazole were higher than the previously determined MICs against planktonic cultures. In contrast, amphotericin B and especially micafungin did not exhibit sufficient antibiofilm activity against L. prolificans. Conclusions To our knowledge, this is the first study demonstrating the antibiofilm potential of olorofim against the human pathogenic fungus L. prolificans.

scholarly journals Caenorhabditis elegans as an Infection Model for Pathogenic Mold and Dimorphic Fungi: Applications and Challenges

2021 ◽  
Vol 11 ◽  
Author(s):  
Chukwuemeka Samson Ahamefule ◽  
Blessing C. Ezeuduji ◽  
James C. Ogbonna ◽  
Anene N. Moneke ◽  
Anthony C. Ike ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Filamentous Fungi ◽  
Virulence Factors ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Infection Model ◽  
Dimorphic Fungi ◽  
C Elegans

The threat burden from pathogenic fungi is universal and increasing with alarming high mortality and morbidity rates from invasive fungal infections. Understanding the virulence factors of these fungi, screening effective antifungal agents and exploring appropriate treatment approaches in in vivo modeling organisms are vital research projects for controlling mycoses. Caenorhabditis elegans has been proven to be a valuable tool in studies of most clinically relevant dimorphic fungi, helping to identify a number of virulence factors and immune-regulators and screen effective antifungal agents without cytotoxic effects. However, little has been achieved and reported with regard to pathogenic filamentous fungi (molds) in the nematode model. In this review, we have summarized the enormous breakthrough of applying a C. elegans infection model for dimorphic fungi studies and the very few reports for filamentous fungi. We have also identified and discussed the challenges in C. elegans-mold modeling applications as well as the possible approaches to conquer these challenges from our practical knowledge in C. elegans-Aspergillus fumigatus model.

scholarly journals Antifungal Pipeline

2021 ◽  
Vol 11 ◽  
Author(s):  
Todd Patrick McCarty ◽  
Peter G. Pappas
Keyword(s):  
Antifungal Agents ◽  
Fungal Infections ◽  
Mechanisms Of Action ◽  
Invasive Fungal Infections ◽  
Fungal Diseases ◽  
Stages Of Development ◽  
The Past ◽  
Clinical Mycology ◽  
Dosing Regimens ◽  
Advanced Stages

In many ways, fungal diseases are forgotten or neglected. Given the significantly lower frequency compared to similar bacterial etiologies across the spectrum of infectious syndromes, it makes sense that anti-bacterial agents have seen the bulk of development in recent decades. The vast majority of new antifungal medications approved for use in the past 10 years have been new versions in the same class as existing agents. Clinical mycology is crying out for new mechanisms of action in the setting of rising resistance and emergence of new organisms. Fortunately, this trend appears to be reversing. There are numerous agents in advanced stages of development offering novel dosing regimens and mechanisms of action to combat these threats. Herein we review seven antifungal agents that we hope to see come to market in the coming years to aid physicians in the treatment of mucocutaneous and invasive fungal infections.

scholarly journals Screening Repurposing Libraries for Identification of Drugs with Novel Antifungal Activity

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Gina Wall ◽  
Jose L. Lopez-Ribot
Keyword(s):  
Antifungal Activity ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Alternative Pathway ◽  
Drug Repurposing ◽  
Pathogenic Fungi ◽  
Multidrug Resistant ◽  
Modern Medicine ◽  
Antifungal Drugs ◽  
Promising Alternative

ABSTRACT Fungal organisms are ubiquitous in nature, and progress of modern medicine is creating an expanding number of severely compromised patients susceptible to a variety of opportunistic fungal infections. These infections are difficult to diagnose and treat, leading to high mortality rates. The limited antifungal arsenal, the toxicity of current antifungal drugs, the development of resistance, and the emergence of new multidrug-resistant fungi, all highlight the urgent need for new antifungal agents. Unfortunately, the development of a novel antifungal is a rather long and expensive proposition, and no new classes of antifungal agents have reached the market in the last 2 decades. Drug repurposing, or finding new indications for old drugs, represents a promising alternative pathway to drug development that is particularly appealing within the academic environment. In the last few years, there has been a growing interest in repurposing approaches in the antifungal arena, with multiple groups of investigators having performed screenings of different repurposing libraries against different pathogenic fungi in search for drugs with previously unrecognized antifungal effects. Overall, these repurposing efforts may lead to the fast deployment of drugs with novel antifungal activity, which can rapidly bring benefits to patients, while at the same time reducing health care costs.

scholarly journals Discovery of Chlorogenic Acid-Based Peptidomimetics as a Novel Class of Antifungals. A Success Story in Rational Drug Design

2008 ◽  
Vol 11 (2) ◽  
pp. 44 ◽  
Author(s):  
Mohsen Daneshtalab
Keyword(s):  
Chlorogenic Acid ◽  
Cyclic Peptides ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Treatment Options ◽  
Pathogenic Fungi ◽  
Current Treatment ◽  
Rational Drug Design ◽  
Synthetic Approach ◽  
Opportunistic Fungi

Life-threatening fungal infections have increased dramatically in recent decades in immunocompromised patients. An estimated 40% of all deaths from hospital-acquired infections are due to infections caused by opportunistic fungi. The current treatment options are either causing serious toxicity, or becoming inactive against the drug-resistant fungal strains. Thus, the discovery and development of new antifungal agents that are economically feasible, have excellent therapeutic value, and address the problems of toxicity and species resistance is very important. We have recently designed and synthesized a series of chlorogenic acid-based peptidimimetics using structure-based methodology starting with cyclic peptides of the candin class of antifungals. These novel and totally synthetic compounds exhibit promising antifungal activity against pathogenic fungi with very low toxicity against brine shrimps. The possible novelty in their mechanism of action and economically feasible synthetic approach are the attractive features of this class of compounds that make them different from the already utilized antifungal agents.

scholarly journals Janus-Faced Molecules against Plant Pathogenic Fungi

2021 ◽  
Vol 22 (22) ◽  
pp. 12323
Author(s):  
Gaspar Banfalvi
Keyword(s):  
Antifungal Agents ◽  
Ethical Issues ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Mutagenic Effect ◽  
Human Pathogens ◽  
Short Term ◽  
High Cytotoxicity ◽  
Apoptotic Effects

The high cytotoxicity of the secondary metabolites of mycotoxins is capable of killing microbes and tumour cells alike, similarly to the genotoxic effect characteristic of Janus-faced molecules. The “double-edged sword” effect of several cytotoxins is known, and these agents have, therefore, been utilized only reluctantly against fungal infections. In this review, consideration was given to (a) toxins that could be used against plant and human pathogens, (b) animal models that measure the effect of antifungal agents, (c) known antifungal agents that have been described and efficiently prevent the growth of fungal cells, and (d) the chemical interactions that are characteristic of antifungal agents. The utilization of apoptotic effects against tumour growth by agents that, at the same time, induce mutations may raise ethical issues. Nevertheless, it deserves consideration despite the mutagenic impact of Janus-faced molecules for those patients who suffer from plant pathogenic fungal infections and are older than their fertility age, in the same way that the short-term cytotoxicity of cancer treatment is favoured over the long-term mutagenic effect.

scholarly journals Transcriptome Assembly and Profiling of Candida auris Reveals Novel Insights into Biofilm-Mediated Resistance

mSphere ◽  
2018 ◽  
Vol 3 (4) ◽  
Author(s):  
Ryan Kean ◽  
Christopher Delaney ◽  
Leighann Sherry ◽  
Andrew Borman ◽  
Elizabeth M. Johnson ◽  
...  
Keyword(s):  
Biofilm Formation ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Transcriptome Assembly ◽  
Efflux Pumps ◽  
Antifungal Drugs ◽  
Hospital Environment ◽  
Planktonic Cells ◽  
Candida Auris ◽  
Content Type

ABSTRACT Candida auris has emerged as a significant global nosocomial pathogen. This is primarily due to its antifungal resistance profile but also its capacity to form adherent biofilm communities on a range of clinically important substrates. While we have a comprehensive understanding of how other Candida species resist and respond to antifungal challenge within the sessile phenotype, our current understanding of C. auris biofilm-mediated resistance is lacking. In this study, we are the first to perform transcriptomic analysis of temporally developing C. auris biofilms, which were shown to exhibit phase- and antifungal class-dependent resistance profiles. A de novo transcriptome assembly was performed, where sequenced sample reads were assembled into an ~11.5-Mb transcriptome consisting of 5,848 genes. Differential expression (DE) analysis demonstrated that 791 and 464 genes were upregulated in biofilm formation and planktonic cells, respectively, with a minimum 2-fold change. Adhesin-related glycosylphosphatidylinositol (GPI)-anchored cell wall genes were upregulated at all time points of biofilm formation. As the biofilm developed into intermediate and mature stages, a number of genes encoding efflux pumps were upregulated, including ATP-binding cassette (ABC) and major facilitator superfamily (MFS) transporters. When we assessed efflux pump activity biochemically, biofilm efflux was greater than that of planktonic cells at 12 and 24 h. When these were inhibited, fluconazole sensitivity was enhanced 4- to 16-fold. This study demonstrates the importance of efflux-mediated resistance within complex C. auris communities and may explain the resistance of C. auris to a range of antimicrobial agents within the hospital environment. IMPORTANCE Fungal infections represent an important cause of human morbidity and mortality, particularly if the fungi adhere to and grow on both biological and inanimate surfaces as communities of cells (biofilms). Recently, a previously unrecognized yeast, Candida auris, has emerged globally that has led to widespread concern due to the difficulty in treating it with existing antifungal agents. Alarmingly, it is also able to grow as a biofilm that is highly resistant to antifungal agents, yet we are unclear about how it does this. Here, we used a molecular approach to investigate the genes that are important in causing the cells to be resistant within the biofilm. The work provides significant insights into the importance of efflux pumps, which actively pump out toxic antifungal drugs and therefore enhance fungal survival within a variety of harsh environments.

Invasive Fungal Infections in the Critically Ill Patient

2005 ◽  
Vol 18 (1) ◽  
pp. 9-17 ◽  
Author(s):  
Craig A. Martin
Keyword(s):  
Critically Ill ◽  
Antifungal Agents ◽  
Clinical Decision Making ◽  
Fungal Infections ◽  
Significant Risk ◽  
Pathogenic Fungi ◽  
Clinical Decision ◽  
Invasive Fungal Infections ◽  
Critically Ill Patient ◽  
Advantages And Disadvantages

Invasive fungal infections have become an increasingly prevalent and disturbing problem in critically ill patients. The advent of broad-spectrum antibacterial therapy and immunosuppressant therapy, among other factors such as mechanical ventilation, places the intensive care patient at significant risk for infection with pathogenic fungi. Most patients who become infected with invasive fungi, especially Candida species, have been previously colonized with the offending organism, lending to the notion that colonization precedes infection inmany cases. Despite an ever-increasing array of antifungal therapy for these infections, mortality rates remain extremely high, especially when the bloodstream is the primary site of infection. In addition, a shift toward more resistant pathogens such asCandida glabrata, Candida krusei, and moldswill provide clinicianswith therapeutic challenges for many years. The wide variation in acquisition cost across antifungal agents adds an additional layer of complexity to clinical decision making. Newer antifungal agents, each with its own advantages and disadvantages, have become available in recent years. Placing each agent in its appropriate niche is a dilemma that has yet to be solved.

scholarly journals Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Andrzej Harris ◽  
Manuel Wagner ◽  
Dijun Du ◽  
Stefanie Raschka ◽  
Lea-Marie Nentwig ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Drug Resistance ◽  
Antifungal Agents ◽  
Pathogenic Fungi ◽  
Drug Efflux ◽  
Antifungal Compounds ◽  
Peristaltic Motion ◽  
Pleiotropic Drug Resistance ◽  
Efflux Mechanism ◽  
Hydrolysis Of

AbstractPdr5, a member of the extensive ABC transporter superfamily, is representative of a clinically relevant subgroup involved in pleiotropic drug resistance. Pdr5 and its homologues drive drug efflux through uncoupled hydrolysis of nucleotides, enabling organisms such as baker’s yeast and pathogenic fungi to survive in the presence of chemically diverse antifungal agents. Here, we present the molecular structure of Pdr5 solved with single particle cryo-EM, revealing details of an ATP-driven conformational cycle, which mechanically drives drug translocation through an amphipathic channel, and a clamping switch within a conserved linker loop that acts as a nucleotide sensor. One half of the transporter remains nearly invariant throughout the cycle, while its partner undergoes changes that are transmitted across inter-domain interfaces to support a peristaltic motion of the pumped molecule. The efflux model proposed here rationalises the pleiotropic impact of Pdr5 and opens new avenues for the development of effective antifungal compounds.

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