Organic Antifungal Drugs and Targets of Their Action

2021 ◽  
Vol 21 ◽  
Author(s):  
Alexander Yu. Maksimov ◽  
Svetlana Yu. Balandina ◽  
Pavel A. Topanov ◽  
Irina V. Mashevskaya ◽  
Sandeep Chaudhary
Keyword(s):  
Molecular Design ◽  
Fungal Infections ◽  
Wide Spectrum ◽  
Molecular Targets ◽  
Antifungal Drugs ◽  
The Body ◽  
Fungal Diseases ◽  
Fungal Cell ◽  
Genomics And Proteomics

: In recent decades, there has been a significant increase in the number of fungal diseases. This is due to a wide spectrum of action, immunosuppressants and other group drugs. In terms of frequency, rapid spread and globality, fungal infections are approaching acute respiratory infections. Antimycotics are medicinal substances endorsed with fungicidal or fungistatic properties. For the treatment of fungal diseases, several groups of compounds are used that differ in their origin (natural or synthetic), molecular targets and mechanism of action, antifungal effect (fungicidal or fungistatic), indications for use (local or systemic infections), methods of administration (parenteral, oral, outdoor). Several efforts have been made by various medicinal chemists around the world for the development of antifungal drugs with high efficacy with least toxicity and maximum selectivity in the area of antifungal chemotherapy. The pharmacokinetic properties of the new antimycotics are also important: the ability to penetrate biological barriers, be absorbed and distributed in tissues and organs, get accumulated in tissues affected by micromycetes, drug metabolism in the intestinal microflora and human organs, and in the kinetics of excretion from the body. There are several ways to search for new effective antimycotics: - Obtaining new derivatives of the already used classes of antimycotics with improved activity properties. - Screening of new chemical classes of synthetic antimycotic compounds. - Screening of natural compounds. - Identification of new unique molecular targets in the fungal cell. - Development of new compositions and dosage forms with effective delivery vehicles. The methods of informatics, bioinformatics, genomics and proteomics were extensively investigated for the development of new antimycotics. These techniques were employed in finding and identification of new molecular proteins in a fungal cell; in the determination of the selectivity of drug-protein interactions, evaluation of drug-drug interactions and synergism of drugs; determination of the structure-activity relationship (SAR) studies; determination of the molecular design of the most active, selective and safer drugs for the humans, animals and plants. In medical applications, the methods of information analysis and pharmacogenomics allows to take into account the individual phenotype of the patient, the level of expression of the targets of antifungal drugs when choosing antifungal agents and its dosage. This review article incorporates some of the most significant studies covering the basic structures and approaches for the synthesis of antifungal drugs and the directions for their further development.

Rapid determination of binding parameters of chitin binding domains using chitin-coated quartz crystal microbalance sensor chips

The Analyst ◽  
2018 ◽  
Vol 143 (21) ◽  
pp. 5255-5263 ◽  
Author(s):  
Stephan Vogt ◽  
Marco Kelkenberg ◽  
Tanja Nöll ◽  
Benedikt Steinhoff ◽  
Holger Schönherr ◽  
...  
Keyword(s):  
Cell Walls ◽  
Quartz Crystal ◽  
Fungal Infections ◽  
Rapid Determination ◽  
Binding Parameters ◽  
Fungal Cell ◽  
Binding Domains ◽  
Quartz Crystal Microbalance Sensor ◽  
Fungal Cell Walls

Chitin present in fungal cell walls has been considered as a diagnostic polymer for the detection of fungal infections.

scholarly journals Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids

mBio ◽  
2015 ◽  
Vol 6 (3) ◽  
Author(s):  
Visesato Mor ◽  
Antonella Rella ◽  
Amir M. Farnoud ◽  
Ashutosh Singh ◽  
Mansa Munshi ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Antifungal Drugs ◽  
Sequencing Analysis ◽  
Fungal Cell ◽  
New Class ◽  
Narrow Spectrum

ABSTRACT Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [N′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo-N′-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5, COS111, MKK1, and STE2, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM. IMPORTANCE Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.

scholarly journals Outstanding Contributions of LAL Technology to Pharmaceutical and Medical Science: Review of Methods, Progress, Challenges, and Future Perspectives in Early Detection and Management of Bacterial Infections and Invasive Fungal Diseases

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 536
Author(s):  
Hiroshi Tamura ◽  
Johannes Reich ◽  
Isao Nagaoka
Keyword(s):  
Bacterial Infections ◽  
Horseshoe Crab ◽  
Fungal Infections ◽  
Medical Science ◽  
Fungal Diseases ◽  
Analytical Sensitivity ◽  
Pharmaceutical Drugs ◽  
Fungal Cell ◽  
Invasive Fungal Diseases ◽  
Lal Assay

The blue blood of the horseshoe crab is a natural, irreplaceable, and precious resource that is highly valued by the biomedical industry. The Limulus amebocyte lysate (LAL) obtained from horseshoe crab blood cells functions as a surprisingly sophisticated sensing system that allows for the extremely sensitive detection of bacterial and fungal cell-wall components. Notably, LAL tests have markedly contributed to the quality control of pharmaceutical drugs and medical devices as successful alternatives to the rabbit pyrogen test. Furthermore, LAL-based endotoxin and (1→3)-β-D-glucan (β-glucan) assay techniques are expected to have optimal use as effective biomarkers, serving as adjuncts in the diagnosis of bacterial sepsis and fungal infections. The innovative β-glucan assay has substantially contributed to the early diagnosis and management of invasive fungal diseases; however, the clinical significance of the endotoxin assay remains unclear and is challenging to elucidate. Many obstacles need to be overcome to enhance the analytical sensitivity and clinical performance of the LAL assay in detecting circulating levels of endotoxin in human blood. Additionally, there are complex interactions between endotoxin molecules and blood components that are attributable to the unique physicochemical properties of lipopolysaccharide (LPS). In this regard, while exploring the potential of new LPS-sensing technologies, a novel platform for the ultrasensitive detection of blood endotoxin will enable a reappraisal of the LAL assay for the highly sensitive and reliable detection of endotoxemia.

scholarly journals Nanoarchitectures in Management of Fungal Diseases: An Overview

2021 ◽  
Vol 11 (15) ◽  
pp. 7119
Author(s):  
Vijay Mishra ◽  
Manvendra Singh ◽  
Yachana Mishra ◽  
Nitin Charbe ◽  
Pallavi Nayak ◽  
...  
Keyword(s):  
Polymer Nanocomposites ◽  
Metallic Nanoparticles ◽  
Antifungal Agents ◽  
Carbon Nanomaterials ◽  
Fungal Infections ◽  
Polymeric Nanoparticles ◽  
Treatment Strategies ◽  
Chemical Compounds ◽  
Antifungal Drugs ◽  
Fungal Diseases

Fungal infections, from mild itching to fatal infections, lead to chronic diseases and death. Antifungal agents have incorporated chemical compounds and natural products/phytoconstituents in the management of fungal diseases. In contrast to antibacterial research, novel antifungal drugs have progressed more swiftly because of their mild existence and negligible resistance of infections to antifungal bioactivities. Nanotechnology-based carriers have gained much attention due to their magnificent abilities. Nanoarchitectures have served as excellent carriers/drug delivery systems (DDS) for delivering antifungal drugs with improved antifungal activities, bioavailability, targeted action, and reduced cytotoxicity. This review outlines the different fungal diseases and their treatment strategies involving various nanocarrier-based techniques such as liposomes, transfersomes, ethosomes, transethosomes, niosomes, spanlastics, dendrimers, polymeric nanoparticles, polymer nanocomposites, metallic nanoparticles, carbon nanomaterials, and nanoemulsions, among other nanotechnological approaches.

scholarly journals Aiming for a bull’s-eye: Targeting antifungals to fungi with dectin-decorated liposomes

2021 ◽  
Vol 17 (7) ◽  
pp. e1009699
Author(s):  
Richard B. Meagher ◽  
Zachary A. Lewis ◽  
Suresh Ambati ◽  
Xiaorong Lin
Keyword(s):  
Organ Transplant ◽  
Drug Efficacy ◽  
The United States ◽  
Antifungal Drugs ◽  
Fungal Diseases ◽  
Antifungal Drug ◽  
Fungal Cell ◽  
Liposomal Drug ◽  
Invasive Fungal Diseases

Globally, there are several million individuals with life-threatening invasive fungal diseases such as candidiasis, aspergillosis, cryptococcosis, Pneumocystis pneumonia (PCP), and mucormycosis. The mortality rate for these diseases generally exceeds 40%. Annual medical costs to treat these invasive fungal diseases in the United States exceed several billion dollars. In addition to AIDS patients, the risks of invasive mycoses are increasingly found in immune-impaired individuals or in immunosuppressed patients following stem cell or organ transplant or implantation of medical devices. Current antifungal drug therapies are not meeting the challenge, because (1) at safe doses, they do not provide sufficient fungal clearance to prevent reemergence of infection; (2) most become toxic with extended use; (3) drug-resistant fungal isolates are emerging; and (4) only one new class of antifungal drugs has been approved for clinical use in the last 2 decades. DectiSomes represent a novel design of drug delivery to drastically increase drug efficacy. Antifungals packaged in liposomes are targeted specifically to where the pathogen is, through binding to the fungal cell walls or exopolysaccharide matrices using the carbohydrate recognition domains of pathogen receptors. Relative to untargeted liposomal drug, DectiSomes show order of magnitude increases in the binding to and killing of Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus in vitro and similarly improved efficacy in mouse models of pulmonary aspergillosis. DectiSomes have the potential to usher in a new antifungal drug treatment paradigm.

scholarly journals Targeting Unconventional Pathways in Pursuit of Novel Antifungals

2021 ◽  
Vol 7 ◽  
Author(s):  
Stephanie Nguyen ◽  
Jia Q. Truong ◽  
John B. Bruning
Keyword(s):  
Small Molecules ◽  
Metabolic Pathways ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Public Health Issue ◽  
Fungal Cell ◽  
Nucleotide Biosynthesis ◽  
Frequent Use ◽  
Drug Classes ◽  
The Impact

The impact of invasive fungal infections on human health is a serious, but largely overlooked, public health issue. Commonly affecting the immunocompromised community, fungal infections are predominantly caused by species of Candida, Cryptococcus, and Aspergillus. Treatments are reliant on the aggressive use of pre-existing antifungal drug classes that target the fungal cell wall and membrane. Despite their frequent use, these drugs are subject to unfavorable drug-drug interactions, can cause undesirable side-effects and have compromised efficacy due to the emergence of antifungal resistance. Hence, there is a clear need to develop novel classes of antifungal drugs. A promising approach involves exploiting the metabolic needs of fungi by targeted interruption of essential metabolic pathways. This review highlights potential antifungal targets including enolase, a component of the enolase-plasminogen complex, and enzymes from the mannitol biosynthesis and purine nucleotide biosynthesis pathways. There has been increased interest in the enzymes that comprise these particular pathways and further investigation into their merits as antifungal targets and roles in fungal survival and virulence are warranted. Disruption of these vital processes by targeting unconventional pathways with small molecules or antibodies may serve as a promising approach to discovering novel classes of antifungals.

scholarly journals Fungal Diseases in the 21st Century: The Near and Far Horizons

2018 ◽  
Vol 3 (2) ◽  
pp. 183 ◽  
Author(s):  
Arturo Casadevall
Keyword(s):  
21St Century ◽  
Fungal Infections ◽  
Medical Problem ◽  
Modern Medicine ◽  
Antifungal Drugs ◽  
Fungal Diseases ◽  
New Drugs ◽  
Medical Mycology ◽  
Research Investment ◽  
Causative Agents

Fungal diseases became a major medical problem in the second half of the 20th century when advances in modern medicine together with the HIV epidemic resulted in large numbers of individuals with impaired immunity. Fungal diseases are difficult to manage because they tend to be chronic, hard to diagnose, and difficult to eradicate with antifungal drugs. This essay considers the future of medical mycology in the 21st century, extrapolating from current trends. In the near horizon, the prevalence of fungal diseases is likely to increase, as there will be more hosts with impaired immunity and drug resistance will inevitably increase after selection by antifungal drug use. We can expect progress in the development of new drugs, diagnostics, vaccines, and immunotherapies. In the far horizon, humanity may face new fungal diseases in association with climate change. Some current associations between chronic diseases and fungal infections could lead to the establishment of fungi as causative agents, which will greatly enhance their medical importance. All trends suggest that the importance of fungal diseases will increase in the 21st century, and enhanced human preparedness for this scourge will require more research investment in this group of infectious diseases.

Molecular targets for new antifungal drugs

1995 ◽  
Vol 73 (S1) ◽  
pp. 1187-1191 ◽  
Author(s):  
John R. Perfect
Keyword(s):  
Molecular Modeling ◽  
Molecular Biology ◽  
Key Words ◽  
Cryptococcus Neoformans ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Molecular Targets ◽  
Model System ◽  
Antifungal Drugs ◽  
Invasive Mycoses

Fungal infections in man and animals have a significant impact on health. However, there are only a few antifungal agents available for treatment of invasive mycoses. Further understanding of fungal molecular pathogenesis in collaboration with biochemistry and molecular modeling strategies should be able to develop new selective fungicidal agents. An example of this approach is Cryptococcus neoformans, which is reviewed in this discussion, as a model system for identification of antifungal molecular targets. Key words: antifungals, fungi, treatment, cryptococcosis, molecular biology, targets.

scholarly journals Amphotericin B, the Wonder of Today’s Pharmacology Science: Persisting Usage for More Than Seven Decades

2020 ◽  
Author(s):  
Falah Hasan Obayes AL-Khikani
Keyword(s):  
Adverse Effects ◽  
Fungal Infection ◽  
Amphotericin B ◽  
Antimicrobial Agents ◽  
Fungal Infections ◽  
Wide Spectrum ◽  
Antifungal Drugs ◽  
Systemic Fungal Infection

Background: Despite several available topical and systemic antifungal drugs for the treatment of fungal infections, Amphotericin B (AmB) is still one of the most common first-line choices in treating systemic fungal infection for more than seven decades after its discovery.  Objectives: Amphotericin B which belongs to the polyene group has a wide spectrum of in vitro and in vivo antifungal activity. Its mechanism of antifungal action is characterized by creating a pore in the fungal plasma membrane leading to cell death. Methods: In addition to the old formula of deoxycholate-Amphotericin B (D-AmB), three lipid formulas have been developed to reduce the adverse effects of conventional AmB (D-AmB) in the human body and increase its therapeutic efficacy. All of the known available formulas of AmB are administrated via intravenous injection to treat severe systemic fungal infections, while the development of the topical formula of AmB is still under preliminary research. Numerous pharmaceutical formulas of systemic and topical applications with clinical uses of AmB in just humans, not in vitro or animals model, against various fungal infections are discussed in this review. Topical AmB formulas are a promising way to develop effective management and to reduce the adverse effects of intravenous formulas of AmB without laboratory monitoring. Results: The wonderful pharmacological properties of AmB with its prolonged use for about seven decades may help researchers to apply its unique features on other various antimicrobial agents by more understanding about the AmB mechanisms of actions. Conclusion: Amphotericin B is widely used intravenously for the treatment of systemic fungal infection, while the topical formula of AmB is still under experimental study. 

scholarly journals Antifungal Polymeric Materials and Nanocomposites

2021 ◽  
Vol 9 ◽  
Author(s):  
Winnie Ntow-Boahene ◽  
David Cook ◽  
Liam Good
Keyword(s):  
Cell Membrane ◽  
Small Molecule ◽  
Plant Pathogens ◽  
Fungal Infections ◽  
Synergistic Effects ◽  
Polymeric Materials ◽  
Antifungal Drugs ◽  
Candida Spp ◽  
Fungal Cell ◽  
Antimicrobial Polymers

Rising global populations due to medicinal advancements increases the patient population susceptible to superficial and severe fungal infections. Fungi often implicated in these diseases includes the dermatophytes (Microsporum spp., Epidermophtyon spp., Trichophyton spp.) as well as species of the Candida spp., Aspergillosis spp. and Cryptococcus spp. genera. In addition, increasing global populations leads to increasing agricultural demands. Thus, fungal infections of preharvested crops and stored food by plant pathogens such as Magnaporthe oryzae and Fusarium oxysporum can have detrimental socioeconomic effects due to food insecurity. Current antifungal strategies are based mainly on small molecule antifungal drugs. However, these drugs are limited by poor solubility and bioavailability. Furthermore, antifungal resistance against these drugs are on the rise. Thus, antimicrobial polymers offer an alternative antifungal strategy. Antifungal polymers are characterised by cationic and hydrophobic regions where the cationic regions have been shown to interact with microbial phospholipids and membranes. These polymers can be synthetic or natural and demonstrate distinct antifungal mechanisms ranging from fungal cell membrane permeabilisation, cell membrane depolarisation or cell entry. Although the relative importance of such mechanisms is difficult to decipher. Due to the chemical properties of these polymers, they can be combined with other antimicrobial compounds including existing antifungal drugs, charcoals, lipids and metal ions to elicit synergistic effects. In some cases, antifungal polymers and nanocomposites show better antifungal effects or reduced toxicity compared to the widely used small molecule antifungal drugs. This review provides an overview of antimicrobial polymers and nanocomposites with antifungal activity and the current understanding of their antifungal mechanisms.

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