scholarly journals New Biological Targets in Fungi and Novel Molecule under Development: A Review

2021 ◽  
pp. 10-21
Author(s):  
Songuigama Coulibaly ◽  
Jean-Paul D. U. N'guessan ◽  
Alain Kacou ◽  
Jean-Fabrice K. Koffi ◽  
Amelanh S. Diakité ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Histone Deacetylases ◽  
Fungal Infections ◽  
Fatty Acid Desaturase ◽  
Antifungal Drugs ◽  
Biological Targets ◽  
Urgent Task ◽  
Terminal Proteins ◽  
Homoserine Transacetylase ◽  
Sphingolipid Biosynthesis

Antifungal therapeutics is confronted today with the challenge of drug resistance of most fungal germs to current antifungal drugs. Faced with this situation, the search for new and more efficient antifungal molecules that avoid the phenomenon of drug resistance becomes an urgent task. The design of new antifungal drugs acting on new biological targets and/or by innovative mechanisms of action is essential in the fight against fungal infections. Current advances in molecular biology have identified new targets for the development of new antifungal therapy. Several biological targets for the development of new antifungal agents are currently being explored. Amongst these, the most promising are BET (Bromodomain and Extra-Terminal) proteins, Homoserine transacetylase (HTA), mannan cell wall, Glycosylphosphatidylinositols (GPI) anchor biosynthesis, Histone deacetylases, Sphingolipid biosynthesis, D9 fatty acid desaturase and Chitin biosynthesis. This review summarizes the new biological targets and their inhibitors under development as potential new antifungal drugs.

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 Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens

Genes ◽  
2018 ◽  
Vol 9 (9) ◽  
pp. 461 ◽  
Author(s):  
Ewa Ksiezopolska ◽  
Toni Gabaldón
Keyword(s):  
Drug Resistance ◽  
Fungal Infections ◽  
Current Knowledge ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Developed Countries ◽  
Antifungal Drugs ◽  
Opportunistic Pathogens ◽  
Evolutionary Mechanisms

Fungal infections, such as candidiasis caused by Candida, pose a problem of growing medical concern. In developed countries, the incidence of Candida infections is increasing due to the higher survival of susceptible populations, such as immunocompromised patients or the elderly. Existing treatment options are limited to few antifungal drug families with efficacies that vary depending on the infecting species. In this context, the emergence and spread of resistant Candida isolates are being increasingly reported. Understanding how resistance can evolve within naturally susceptible species is key to developing novel, more effective treatment strategies. However, in contrast to the situation of antibiotic resistance in bacteria, few studies have focused on the evolutionary mechanisms leading to drug resistance in fungal species. In this review, we will survey and discuss current knowledge on the genetic bases of resistance to antifungal drugs in Candida opportunistic pathogens. We will do so from an evolutionary genomics perspective, focusing on the possible evolutionary paths that may lead to the emergence and selection of the resistant phenotype. Finally, we will discuss the potential of future studies enabled by current developments in sequencing technologies, in vitro evolution approaches, and the analysis of serial clinical isolates.

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.

Exploration of Medicinal Plants as Sources of Novel Anticandidal Drugs

2019 ◽  
Vol 19 (28) ◽  
pp. 2579-2592
Author(s):  
Ajay Kumar ◽  
Feroz Khan ◽  
Dharmendra Saikia
Keyword(s):  
Drug Resistance ◽  
Medicinal Plants ◽  
Fungal Infections ◽  
Relevant Information ◽  
Antifungal Drugs ◽  
Fungal Strains ◽  
Efficient Management ◽  
Mucosal Surfaces ◽  
Human Infections ◽  
Anti Fungal

Background: : Human infections associated with skin and mucosal surfaces, mainly in tropical and sub-tropical parts of the world. During the last decade, there have been an increasing numbers of cases of fungal infections in immunocompromised patients, coupled with an increase in the number of incidences of drug resistance and toxicity to anti fungal agents. Hence, there is a dire need for safe, potent and affordable new antifungal drugs for the efficient management of candidal infections with minimum or no side effects. Introduction: : Candidiasis represents a critical problem to human health and a serious concern worldwide. Due to the development of drug resistance, there is a need for new antifungal agents. Therefore, we reviewed the different medicinal plants as sources of novel anticandidal drugs. Methods: : The comprehensive and detailed literature on medicinal plants was carried out using different databases, such as Google Scholar, PubMed, and Science Direct and all the relevant information from the articles were analyzed and included. Result: : Relevant Publications up to the end of November 2018, reporting anticandidal activity of medicinal plants has been included in the present review. In the present study, we have reviewed in the light of SAR and mechanisms of action of those plants whose extracts or phytomolecules are active against candida strains. Conclusion:: This article reviewed natural anticandidal drugs of plant origin and also summarized the potent antifungal bioactivity against fungal strains. Besides, mechanism of action of these potent active plant molecules was also explored for a comparative study. We concluded that the studied active plant molecules exhibit potential antifungal activity against resistant fungal strains.

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 Antifungal Drug Development: Targeting the Fungal Sphingolipid Pathway

2020 ◽  
Vol 6 (3) ◽  
pp. 142
Author(s):  
Kyle McEvoy ◽  
Tyler G. Normile ◽  
Maurizio Del Poeta
Keyword(s):  
Drug Resistance ◽  
Drug Development ◽  
Mechanism Of Action ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Antifungal Compounds ◽  
Metabolizing Enzymes ◽  
Progressive Development

Fungal infections are becoming more prevalent and problematic due to the continual rise of immune deficient patients as well as the progressive development of drug resistance towards currently available antifungal drugs. There has been a significant increase in the development of antifungal compounds with a similar mechanism of action of current drugs. In contrast, there has been very little progress in developing compounds inhibiting totally new fungal targets or/and fungal pathways. This review focuses on novel compounds recently discovered to target the fungal sphingolipids and their metabolizing enzymes.

scholarly journals Amphotericin B and Other Polyenes—Discovery, Clinical Use, Mode of Action and Drug Resistance

2020 ◽  
Vol 6 (4) ◽  
pp. 321
Author(s):  
Hans Carolus ◽  
Siebe Pierson ◽  
Katrien Lagrou ◽  
Patrick Van Dijck
Keyword(s):  
Drug Resistance ◽  
Amphotericin B ◽  
Mode Of Action ◽  
Fungal Infections ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
Clinical Use ◽  
Candida Auris ◽  
Resistance Development ◽  
Resistant Species

Although polyenes were the first broad spectrum antifungal drugs on the market, after 70 years they are still the gold standard to treat a variety of fungal infections. Polyenes such as amphotericin B have a controversial image. They are the antifungal drug class with the broadest spectrum, resistance development is still relatively rare and fungicidal properties are extensive. Yet, they come with a significant host toxicity that limits their use. Relatively recently, the mode of action of polyenes has been revised, new mechanisms of drug resistance were discovered and emergent polyene resistant species such as Candida auris entered the picture. This review provides a short description of the history and clinical use of polyenes, and focusses on the ongoing debate concerning their mode of action, the diversity of resistance mechanisms discovered to date and the most recent trends in polyene resistance development.

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 Striking Back against Fungal Infections: The Utilization of Nanosystems for Antifungal Strategies

2021 ◽  
Vol 22 (18) ◽  
pp. 10104
Author(s):  
Wei Du ◽  
Yiru Gao ◽  
Li Liu ◽  
Sixiang Sai ◽  
Chen Ding
Keyword(s):  
Drug Delivery ◽  
Drug Resistance ◽  
Water Solubility ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Aspergillus Species ◽  
Health Concern ◽  
Tissue Penetration ◽  
Major Health ◽  
Invasive Infections

Fungal infections have become a major health concern, given that invasive infections by Candida, Cryptococcus, and Aspergillus species have led to millions of mortalities. Conventional antifungal drugs including polyenes, echinocandins, azoles, allylamins, and antimetabolites have been used for decades, but their limitations include off-target toxicity, drug-resistance, poor water solubility, low bioavailability, and weak tissue penetration, which cannot be ignored. These drawbacks have led to the emergence of novel antifungal therapies. In this review, we discuss the nanosystems that are currently utilized for drug delivery and the application of antifungal therapies.

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.

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