scholarly journals Isavuconazole: Mechanism of Action, Clinical Efficacy, and Resistance

2020 ◽  
Vol 6 (4) ◽  
pp. 324
Author(s):  
Misti Ellsworth ◽  
Luis Ostrosky-Zeichner
Keyword(s):  
Antifungal Agents ◽  
Fungal Infections ◽  
Alternative Therapy ◽  
Salvage Treatment ◽  
Cross Resistance ◽  
Dimorphic Fungi ◽  
Risk Patients ◽  
Favorable Safety ◽  
Immunocompromised Hosts

Increasing incidence of invasive fungal infections combined with a growing population of immunocompromised hosts has created a rising need for antifungal agents. Isavuconazole, a second-generation broad-spectrum triazole with activity against yeasts, dimorphic fungi, and molds, has a favorable safety profile and predictable pharmacokinetics. Patients typically tolerate isavuconazole well with fewer drug–drug interactions. Clinical trials have found it to be noninferior to voriconazole for invasive aspergillosis, an alternative therapy for salvage treatment of mucormycosis, and suitable for stepdown therapy with invasive candidiasis. Cross-resistance with other triazoles is common. More studies are needed to determine the role of isavuconazole in anti-mold prophylaxis in high-risk patients.

scholarly journals Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Juliana Alves Parente-Rocha ◽  
Alexandre Melo Bailão ◽  
André Correa Amaral ◽  
Carlos Pelleschi Taborda ◽  
Juliano Domiraci Paccez ◽  
...  
Keyword(s):  
Drug Targets ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Public Health Problem ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Immunocompromised Patients ◽  
Dimorphic Fungi ◽  
Novel Drug ◽  
Novel Drug Targets

Diseases caused by fungi can occur in healthy people, but immunocompromised patients are the major risk group for invasive fungal infections. Cases of fungal resistance and the difficulty of treatment make fungal infections a public health problem. This review explores mechanisms used by fungi to promote fungal resistance, such as the mutation or overexpression of drug targets, efflux and degradation systems, and pleiotropic drug responses. Alternative novel drug targets have been investigated; these include metabolic routes used by fungi during infection, such as trehalose and amino acid metabolism and mitochondrial proteins. An overview of new antifungal agents, including nanostructured antifungals, as well as of repositioning approaches is discussed. Studies focusing on the development of vaccines against antifungal diseases have increased in recent years, as these strategies can be applied in combination with antifungal therapy to prevent posttreatment sequelae. Studies focused on the development of a pan-fungal vaccine and antifungal drugs can improve the treatment of immunocompromised patients and reduce treatment costs.

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 Targeted Gene Disruption Reveals an Adhesin Indispensable for Pathogenicity of Blastomyces dermatitidis

1999 ◽  
Vol 189 (8) ◽  
pp. 1207-1216 ◽  
Author(s):  
T. Tristan Brandhorst ◽  
Marcel Wüthrich ◽  
Thomas Warner ◽  
Bruce Klein
Keyword(s):  
Gene Transfer ◽  
Gene Disruption ◽  
Reverse Genetics ◽  
Fungal Infections ◽  
Blastomyces Dermatitidis ◽  
Dimorphic Fungi ◽  
Targeted Gene Disruption ◽  
Allelic Replacement ◽  
Impaired Binding

Systemic fungal infections are becoming more common and difficult to treat, yet the pathogenesis of these infectious diseases remains poorly understood. In many cases, pathogenicity can be attributed to the ability of the fungi to adhere to target tissues, but the lack of tractable genetic systems has limited progress in understanding and interfering with the offending fungal products. In Blastomyces dermatitidis, the agent of blastomycosis, a respiratory and disseminated mycosis of people and animals worldwide, expression of the putative adhesin encoded by the WI-1 gene was investigated as a possible virulence factor. DNA-mediated gene transfer was used to disrupt the WI-1 locus by allelic replacement, resulting in impaired binding and entry of yeasts into macrophages, loss of adherence to lung tissue, and abolishment of virulence in mice; each of these properties was fully restored after reconstitution of WI-1 by means of gene transfer. These findings establish the pivotal role of WI-1 in adherence and virulence of B. dermatitidis yeasts. To our knowledge, they offer the first example of a genetically proven virulence determinant among systemic dimorphic fungi, and underscore the value of reverse genetics for studies of pathogenesis in these organisms.

scholarly journals The ROLE OF HERBAL ANTIFUNGAL AGENTS FOR THE MANAGEMENT OF FUNGAL DISEASES: A SYSTEMATIC REVIEW

2019 ◽  
pp. 34-40
Author(s):  
KUSUM KAUSHIK ◽  
SHWETA AGARWAL
Keyword(s):  
Antifungal Agents ◽  
Fungal Infections ◽  
Geographical Area ◽  
Candida Spp ◽  
Helminthic Infections ◽  
Specific Geographical Area ◽  
Malassezia Folliculitis ◽  
Plant Constituents ◽  
Natural Medicines

Nowadays, fungal infection of skin is one of the most common dermatological problems worldwide. It has been investigated that 40 million people suffer from fungal infections. Superficial and subcutaneous fungal infections affect the skin, keratinous tissues, and mucous membranes. The dermatophytic infections, superficial candidiasis of the mouth, skin, or genital tract and infections due to Malassezia, such as pityriasis versicolor and Malassezia folliculitis are the main afflicting conditions. Systemic fungal infections may be caused by either an opportunistic organism that infects an at-risk host or may be associated with a more invasive organism or may be endemic to a specific geographical area. The most frequently encountered pathogens are Candida albicans and Aspergillus spp. but other fungi such as non-albicans Candida spp. are increasingly important in causing systemic fungal infections. There are numerous antifungal agents used clinically to treat fungal infections, i.e., azoles, allylamines, echinocandins, griseofulvin, and flucytosine. The course to modern treatment has not been without its problems and complications, particularly the drug resistances. Phytochemistry of various plant species has indicated that the phytochemicals could be a better source of medicine as compared to synthetically produced drugs. Natural medicines from a plant origin are still used as therapeutic agents, especially for treating bacterial, fungal, viral, protozoal, helminthic infections, etc. This review focuses on the use of plant constituents to prevent fungal infections caused by various pathogens. Hence, it will be proved beneficial for the drug industries.

scholarly journals APX001 and Other Gwt1 Inhibitor Prodrugs Are Effective in ExperimentalCoccidioides immitisPneumonia

2018 ◽  
Vol 63 (2) ◽  
pp. e01715-18 ◽  
Author(s):  
Suganya Viriyakosol ◽  
Mili Kapoor ◽  
Sharon Okamoto ◽  
Jonathan Covel ◽  
Quinlyn A. Soltow ◽  
...  
Keyword(s):  
Antifungal Agents ◽  
Fungal Infections ◽  
Hyphal Growth ◽  
Western Hemisphere ◽  
Great Promise ◽  
Human Pharmacokinetics ◽  
Coccidioides Immitis ◽  
Dimorphic Fungi ◽  
Content Type ◽  
New Class

ABSTRACTCoccidioidomycosis is a systemic fungal infection caused by the inhalation of the arthroconidia of either of two closely related dimorphic fungi,Coccidioides immitisandC. posadasii, that are endemic in the southwestern United States and other areas in the Western Hemisphere. Chronic cavitary pulmonary infections and extrapulmonary sites of infection are very difficult to treat and often require lifelong azole therapy. APX001A is the first in a new class of broad-spectrum antifungal agents that inhibit Gwt1, an enzyme which is required for cell wall localization of glycosylphosphatidylinositol (GPI)-anchored mannoproteins in fungi. APX001A and several analogs were highly active against clinical isolates ofCoccidioides, inhibiting hyphal growth at low nanogram/ml concentrations. APX001 is the N-phosphonooxymethyl prodrug of APX001A, currently in clinical trials for the treatment of invasive fungal infections. Mice were treated orally once daily with 26 mg/kg/day of APX001 and the prodrug analog APX2097, 2 h after administration of the pan-cytochrome P450 inhibitor 1-aminobenzotriazole, which was used to enhance drug half-life and exposures to more closely mimic human pharmacokinetics of APX001A. Five days of treatment reduced lung colony counts by nearly 3 logs and prevented dissemination, similar to the efficacy of fluconazole dosed orally at 25 mg/kg twice daily. In a survival experiment, both APX001- and APX2097-treated mice survived significantly longer than control and fluconazole-treated mice. APX001 and other members of this new class of antifungal agents may offer great promise as effective therapies for coccidioidomycosis.

scholarly journals Pseudomonas aeruginosainhibitsRhizopus microsporusgermination through sequestration of free environmental iron

2018 ◽  
Author(s):  
Courtney Kousser ◽  
Callum Clark ◽  
Kerstin Voelz ◽  
Rebecca A. Hall
Keyword(s):  
Fungal Infections ◽  
Fungal Spores ◽  
Fungal Growth ◽  
Antibacterial Treatment ◽  
Nutrient Restriction ◽  
Rhizopus Microsporus ◽  
Risk Patients ◽  
Host Mortality ◽  
Etiological Agents

AbstractRhizopus sppare the most common etiological agents of mucormycosis, causing over 90% mortality in disseminated infection. Key to pathogenesis is the ability of fungal spores to swell, germinate, and penetrate surrounding tissues. Antibiotic treatment in at-risk patients increases the probability of the patient developing mucormycosis, suggesting that bacteria have the potential to control the growth of the fungus. However, research into polymicrobial relationships involvingRhizopus spphas not been extensively explored. Here we show that co-culturingRhizopus microsporusandPseudomonas aeruginosaresults in the inhibition of spore germination. This inhibition was mediated via the secretion of bacterial siderophores, confirming the essential role of iron for fungal growth. Addition ofP. aeruginosasiderophores toR. microsporusspores in the zebrafish larval model of infection resulted in inhibition of fungal germination and reduced host mortality. Therefore, during infection antibacterial treatment may relieve bacterial imposed nutrient restriction resulting in secondary fungal infections.

scholarly journals Evaluation of Resistance Development to the Gwt1 Inhibitor Manogepix (APX001A) in Candida Species

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Mili Kapoor ◽  
Molly Moloney ◽  
Quinlyn A. Soltow ◽  
Chris M. Pillar ◽  
Karen Joy Shaw
Keyword(s):  
Antifungal Agents ◽  
Fungal Infections ◽  
Fold Increase ◽  
Serial Passage ◽  
Clinical Development ◽  
Cross Resistance ◽  
Biosynthesis Pathway ◽  
Spontaneous Mutations ◽  
Resistance Development ◽  
Content Type

ABSTRACT Manogepix (MGX) targets the conserved fungal Gwt1 enzyme required for acylation of inositol early in the glycosylphosphatidylinositol biosynthesis pathway. The prodrug fosmanogepix is currently in clinical development for the treatment of invasive fungal infections. We determined that the median frequencies of spontaneous mutations conferring reduced susceptibility to MGX in Candida albicans, C. glabrata, and C. parapsilosis ranged from 3 × 10−8 to <1.85 × 10−8. Serial passage on agar identified mutants of C. albicans and C. parapsilosis with reduced susceptibility to MGX; however, this methodology did not result in C. glabrata mutants with reduced susceptibility. Similarly, serial passage in broth resulted in ≤2-fold changes in population MIC values for C. tropicalis, C. auris, and C. glabrata. A spontaneous V163A mutation in the Gwt1 protein of C. glabrata and a corresponding C. albicans heterozygous V162A mutant were obtained. A C. glabrata V163A Gwt1 mutant generated using CRISPR, along with V162A and V168A mutants expressed in C. albicans and Saccharomyces cerevisiae Gwt1, respectively, all demonstrated reduced susceptibility to MGX versus control strains, suggesting the importance of this valine residue to MGX binding across different species. Cross-resistance to the three major classes of antifungals was evaluated, but no changes in susceptibility to amphotericin B or caspofungin were observed in any mutant. No change was observed in fluconazole susceptibility, with the exception of a single non-Gwt1 mutant, where a 4-fold increase in the fluconazole MIC was observed. MGX demonstrated a relatively low potential for resistance development, consistent with other approved antifungal agents and those in clinical development.

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