scholarly journals Immunotherapy against Systemic Fungal Infections Based on Monoclonal Antibodies

2020 ◽  
Vol 6 (1) ◽  
pp. 31 ◽  
Author(s):  
Camila Boniche ◽  
Suélen Andreia Rossi ◽  
Brenda Kischkel ◽  
Filipe Vieira Barbalho ◽  
Ágata Nogueira D’Aurea Moura ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Fungal Infections ◽  
Kidney Injury ◽  
Concomitant Administration ◽  
Experimental Models ◽  
Antifungal Drugs ◽  
Drug Induced ◽  
Efficient Treatment ◽  
Invasive Mycoses

The increasing incidence in systemic fungal infections in humans has increased focus for the development of fungal vaccines and use of monoclonal antibodies. Invasive mycoses are generally difficult to treat, as most occur in vulnerable individuals, with compromised innate and adaptive immune responses. Mortality rates in the setting of our current antifungal drugs remain excessively high. Moreover, systemic mycoses require prolonged durations of antifungal treatment and side effects frequently occur, particularly drug-induced liver and/or kidney injury. The use of monoclonal antibodies with or without concomitant administration of antifungal drugs emerges as a potentially efficient treatment modality to improve outcomes and reduce chemotherapy toxicities. In this review, we focus on the use of monoclonal antibodies with experimental evidence on the reduction of fungal burden and prolongation of survival in in vivo disease models. Presently, there are no licensed monoclonal antibodies for use in the treatment of systemic mycoses, although the potential of such a vaccine is very high as indicated by the substantial promising results from several experimental models.

scholarly journals Nephrotoxicity Biomarkers: Role and Significance in the Diagnosis of Drug-Induced Kidney Injury

2021 ◽  
Vol 9 (4) ◽  
pp. 173-184
Author(s):  
O. V. Muslimova ◽  
V. A. Evteev ◽  
I. A. Mazerkina ◽  
E. A. Sokova ◽  
A. B. Prokofiev ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Experimental Models ◽  
Injury Incidence ◽  
Drug Induced ◽  
Blood Concentrations ◽  
Incidence And Mortality ◽  
Hospital Patients

Drug-induced kidney injury (DIKI) accounts for 8 to 60% of episodes of acute kidney injury (AKI) among hospital patients. Early DIKI detection and timely adjustment of therapy will help reduce the kidney injury incidence and mortality. The aim of the study was to analyse scientific literature on the biomarkers used in DIKI diagnosis. The study revealed that the use of such kidney damage markers as serum creatinine, urinary output, urea nitrogen, sodium excretion, urinary sediment microscopy is limited because they do not give a full picture of the kidney injury degree and progression and do not allow for early AKI diagnosis. It was demonstrated that some of the most promising biomarkers are KIM-1, L-FABP, NAG, NGAL, cystatin C, clusterin, β2-microglobulin, МСР-1, IGFBP7, and TIMP-2. However, recommendations for determination of these biomarkers’ urine or blood concentrations for AKI diagnosis are somewhat preliminary, because there have been insufficient clinical and preclinical studies to establish validity of such tests. No precise algorithms based on determination of the biomarkers levels in urea and/or blood serum have been developed for AKI risk assessment, diagnosis, monitoring, and treatment. Thus, further research is necessary to investigate different AKI biomarkers and improve experimental models (both in vivo and in vitro), which will support assessment of potential nephrotoxic properties of existing and new medicinal products.

scholarly journals Effects of Shiga Toxin Type 2 on a Bioengineered Three-Dimensional Model of Human Renal Tissue

2014 ◽  
Vol 83 (1) ◽  
pp. 28-38 ◽  
Author(s):  
Teresa M. DesRochers ◽  
Erica Palma Kimmerling ◽  
Dakshina M. Jandhyala ◽  
Wassim El-Jouni ◽  
Jing Zhou ◽  
...  
Keyword(s):  
Cell Culture ◽  
Renal Failure ◽  
Shiga Toxin ◽  
Three Dimensional ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Three Dimensional Model ◽  
Drug Induced ◽  
Tissue Model

Shiga toxins (Stx) are a family of cytotoxic proteins that can cause hemolytic-uremic syndrome (HUS), a thrombotic microangiopathy, following infections by Shiga toxin-producingEscherichia coli(STEC). Renal failure is a key feature of HUS and a major cause of childhood renal failure worldwide. There are currently no specific therapies for STEC-associated HUS, and the mechanism of Stx-induced renal injury is not well understood primarily due to a lack of fully representative animal models and an inability to monitor disease progression on a molecular or cellular level in humans at early stages. Three-dimensional (3D) tissue models have been shown to be morein vivo-like in their phenotype and physiology than 2D cultures for numerous disease models, including cancer and polycystic kidney disease. It is unknown whether exposure of a 3D renal tissue model to Stx will yield a morein vivo-like response than 2D cell culture. In this study, we characterized Stx2-mediated cytotoxicity in a bioengineered 3D human renal tissue model previously shown to be a predictor of drug-induced nephrotoxicity and compared its response to Stx2 exposure in 2D cell culture. Our results demonstrate that although many mechanistic aspects of cytotoxicity were similar between 3D and 2D, treatment of the 3D tissues with Stx resulted in an elevated secretion of the kidney injury marker 1 (Kim-1) and the cytokine interleukin-8 compared to the 2D cell cultures. This study represents the first application of 3D tissues for the study of Stx-mediated kidney injury.

scholarly journals Evaluation of biomarkers for in vitro prediction of drug-induced nephrotoxicity in RPTEC/TERT1 cells

2020 ◽  
Vol 9 (2) ◽  
pp. 91-100 ◽  
Author(s):  
Xuan Qiu ◽  
Yufa Miao ◽  
Xingchao Geng ◽  
Xiaobing Zhou ◽  
Bo Li
Keyword(s):  
Transcriptional Activation ◽  
Messenger Rna ◽  
Aristolochic Acid ◽  
Kidney Injury ◽  
Drug Induced ◽  
Vitro Assay ◽  
Protein Levels ◽  
Aristolochic Acid I

Abstract There have been intensive efforts to identify in vivo biomarkers that can be used to monitor drug-induced kidney damage before significant impairment occurs. Kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, clusterin, β2-microglobulin and cystatin C (CysC) have been validated as clinical or preclinical biomarkers in urinary and plasma predictive of acute and chronic kidney injuries and diseases. A high-throughput in vitro assay predictive of nephrotoxicity could potentially be implemented in early drug discovery stage to reduce attrition at later stages of drug development. To assess the potential of these known in vivo biomarkers for in vitro evaluation of drug-induced nephrotoxicity, we selected four nephrotoxic agents (cisplatin, cyclosporin, aristolochic acid I and gentamicin) and detected their effects on the protein levels of nephrotoxic biomarkers in RPTEC/TERT1 cells. The protein levels of clusterin, CysC, GSTπ and TIMP-1 significantly increased in the conditioned media of RPTEC/TERT1 cells treated with cisplatin, cyclosporin, aristolochic acid I and gentamicin. The messenger RNA levels of clusterin, CysC, GSTπ and TIMP-1 also increased in RPTEC/TERT1 cells treated with cisplatin, cyclosporin, aristolochic acid I and gentamicin, indicating that drug-induced upregulation involves transcriptional activation. Taken together, the results clearly demonstrate that among the known in vivo nephrotoxic biomarkers, clusterin, CysC, GSTπ and TIMP-1 can be effectively used as in vitro biomarkers for drug-induced nephrotoxicity in RPTEC/TERT1 cells.

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 Non-toxic Cobalt(III) Schiff Base Complexes with Broad Spectrum Antifungal Activity

2020 ◽  
Author(s):  
Angelo Frei ◽  
A. Paden King ◽  
Gabrielle J. Lowe ◽  
Amy K. Cain ◽  
Francesca L. Short ◽  
...  
Keyword(s):  
Schiff Base ◽  
Antifungal Activity ◽  
Broad Spectrum ◽  
Bacterial Infections ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Schiff Base Complexes ◽  
In Vivo Studies

Resistance to currently available antifungal drugs has quietly been on the rise but overshadowed by the alarming spread of antibacterial resistance. There is a striking lack of attention to the threat of drug resistant fungal infections, with only a handful of new drugs currently in development. Given that metal complexes have proven to be useful new chemotypes in the fight against diseases such as cancer, malaria, and bacterial infections, it stands to reason to explore their possible utility in treating fungal infections. Herein we report a series of cobalt(III) Schiff base complexes with broad spectrum antifungal activity. Some of these complexes (1-3) show minimum inhibitory concentrations (MIC) in the low micro- to nanomolar range against a series of Candida and Cryptococcus yeasts. Additionally, we demonstrate that these compounds show no cytotoxicity against both bacterial and human cells. Finally, we report first in vivo toxicity data on these compounds in Galleria mellonella, showing that doses as high as 266 mg/kg are tolerated without adverse effects, paving the way for further in vivo studies of these complexes. <br>

scholarly journals Antifungal effect of all-trans retinoic acid against Aspergillus fumigatus in vitro and in a pulmonary aspergillosis in vivo model

2020 ◽  
Author(s):  
Elena Campione ◽  
Roberta Gaziano ◽  
Elena Doldo ◽  
Daniele Marino ◽  
Mattia Falconi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Aspergillus Fumigatus ◽  
Rat Model ◽  
Fungal Infections ◽  
Invasive Pulmonary Aspergillosis ◽  
Antifungal Drugs ◽  
Pulmonary Aspergillosis ◽  
Fungistatic Activity

AIM: Aspergillus fumigatus is the most common opportunistic fungal pathogen and causes invasive pulmonary aspergillosis (IPA), with high mortality among immunosuppressed patients. Fungistatic activity of all-trans retinoic acid (ATRA) has been recently described in vitro. We evaluated the efficacy of ATRA in vivo and its potential synergistic interaction with other antifungal drugs. MATERIALS AND METHODS: A rat model of IPA and in vitro experiments were performed to assess the efficacy of ATRA against Aspergillus in association with classical antifungal drugs and in silico studies used to clarify its mechanism of action. RESULTS: ATRA (0.5 and 1 mM) displayed a strong fungistatic activity in Aspergillus cultures, while at lower concentrations, synergistically potentiated fungistatic efficacy of sub-inhibitory concentration of Amphotericin B (AmB) and Posaconazole (POS). ATRA also enhanced macrophagic phagocytosis of conidia. In a rat model of IPA, ATRA reduced mortality similarly to Posaconazole. CONCLUSION: Fungistatic efficacy of ATRA alone and synergistically with other antifungal drugs was documented in vitro, likely by inhibiting fungal Hsp90 expression and Hsp90-related genes. ATRA reduced mortality in a model of IPA in vivo. Those findings suggest ATRA as suitable fungistatic agent, also to reduce dosage and adverse reaction of classical antifungal drugs, and new therapeutic strategies against IPA and systemic fungal infections.

Adult Zebrafish Model for Screening Drug-Induced Kidney Injury

2020 ◽  
Vol 174 (2) ◽  
pp. 241-253 ◽  
Author(s):  
Yuki Kato ◽  
Yutaka Tonomura ◽  
Hiroyuki Hanafusa ◽  
Kyohei Nishimura ◽  
Tamio Fukushima ◽  
...  
Keyword(s):  
Predictive Value ◽  
Safety Issue ◽  
Kidney Injury ◽  
Pathological Examination ◽  
Control Group ◽  
Adult Zebrafish ◽  
Drug Induced ◽  
Zebrafish Model ◽  
Renal Tubular

Abstract Drug-induced kidney injury is a serious safety issue in drug development. In this study, we evaluated the usefulness of adult zebrafish as a small in vivo system for detecting drug-induced kidney injury. We first investigated the effects of typical nephrotoxicants, gentamicin and doxorubicin, on adult zebrafish. We found that gentamicin induced renal tubular necrosis with increased lysosome and myeloid bodies, and doxorubicin caused foot process fusion of glomerular podocytes. These findings were similar to those seen in mammals, suggesting a common pathogenesis. Second, to further evaluate the performance of the model in detecting drug-induced kidney injury, adult zebrafish were treated with 28 nephrotoxicants or 14 nonnephrotoxicants for up to 4 days, euthanized 24 h after the final treatment, and examined histopathologically. Sixteen of the 28 nephrotoxicants and none of the 14 nonnephrotoxicants caused drug-induced kidney injury in zebrafish (sensitivity, 57%; specificity, 100%; positive predictive value, 100%; negative predictive value, 54%). Finally, we explored genomic biomarker candidates using kidneys isolated from gentamicin- and cisplatin-treated zebrafish using microarray analysis and identified 3 candidate genes, egr1, atf3, and fos based on increased expression levels and biological implications. The expression of these genes was upregulated dose dependently in cisplatin-treated groups and was &gt; 25-fold higher in gentamicin-treated than in the control group. In conclusion, these results suggest that the adult zebrafish has (1) similar nephrotoxic response to those of mammals, (2) considerable feasibility as an experimental model for toxicity studies, and (3) applicability to pathological examination and genomic biomarker evaluation in drug-induced kidney injury.

scholarly journals Identification of Essential Genes in the Human Fungal Pathogen Aspergillus fumigatus by Transposon Mutagenesis

2003 ◽  
Vol 2 (2) ◽  
pp. 247-255 ◽  
Author(s):  
Arnaud Firon ◽  
François Villalba ◽  
Roland Beffa ◽  
Christophe d'Enfert
Keyword(s):  
Aspergillus Fumigatus ◽  
Transposable Element ◽  
Drug Targets ◽  
Fungal Infections ◽  
Fungal Growth ◽  
Developed Countries ◽  
Transposon Mutagenesis ◽  
Essential Genes ◽  
Antifungal Drugs

ABSTRACT The opportunistic pathogen Aspergillus fumigatus is the most frequent cause of deadly airborne fungal infections in developed countries. In order to identify novel antifungal-drug targets, we investigated the genome of A. fumigatus for genes that are necessary for efficient fungal growth. An artificial A. fumigatus diploid strain with one copy of an engineered impala160 transposon from Fusarium oxysporum integrated into its genome was used to generate a library of diploid strains by random in vivo transposon mutagenesis. Among 2,386 heterozygous diploid strains screened by parasexual genetics, 1.2% had a copy of the transposable element integrated into a locus essential for A. fumigatus growth. Comparison of genomic sequences flanking impala160 in these mutants with that of the genome of A. fumigatus allowed the characterization of 20 previously uncharacterized A. fumigatus genes. Among these, homologues of genes essential for Saccharomyces cerevisiae growth have been identified, as well as genes that do not have homologues in other fungal species. These results confirm that heterologous transposition using the transposable element impala is a powerful tool for functional genomics in ascomycota, and they pave the way for defining the complete set of essential genes in A. fumigatus, the first step toward target-based development of new antifungal drugs.

scholarly journals Pre-Existing Liver Disease and Toxicity of Antifungals

2018 ◽  
Vol 4 (4) ◽  
pp. 133 ◽  
Author(s):  
Nikolaos Spernovasilis ◽  
Diamantis Kofteridis
Keyword(s):  
Decision Making ◽  
Liver Disease ◽  
Antifungal Agents ◽  
Dosage Adjustment ◽  
Fungal Infections ◽  
Drug Efficacy ◽  
Antifungal Drugs ◽  
Current Evidence ◽  
Comprehensive Review

Pre-existing liver disease in patients with invasive fungal infections further complicates their management. Altered pharmacokinetics and tolerance issues of antifungal drugs are important concerns. Adjustment of the dosage of antifungal agents in these cases can be challenging given that current evidence to guide decision-making is limited. This comprehensive review aims to evaluate the existing evidence related to antifungal treatment in individuals with liver dysfunction. This article also provides suggestions for dosage adjustment of antifungal drugs in patients with varying degrees of hepatic impairment, after accounting for established or emerging pharmacokinetic–pharmacodynamic relationships with regard to antifungal drug efficacy in vivo.

scholarly journals The current place of echinocandins in the treatment and prophylaxis of invasive fungal infections

2020 ◽  
pp. 197-209
Author(s):  
Alexander V. Veselov
Keyword(s):  
Mechanism Of Action ◽  
Fungicidal Activity ◽  
Fungal Infections ◽  
Invasive Fungal Infections ◽  
Antifungal Drugs ◽  
Steady Growth ◽  
Good Safety Profile ◽  
Invasive Mycoses ◽  
Unique Mechanism ◽  
Practical Recommendations

Invasive fungal infections continue to show steady growth among various patient populations, accompanied by high rates of both morbidity and attributive mortality. For the treatment of invasive mycoses, a few number of drugs are currently available, which include polyenes, azoles, echinocandins, allylamines and flucytosine. Among these groups, echinocandins – anidulafungin, caspofungin and mycafungin – represent a key class of antifungal drugs, primarily for the treatment of the most common form of systemic fungal infections – Invasive candidiasis. Possessing a unique mechanism of action that determines fungicidal activity against yeast pathogens, a predictable pharmacokinetics profile, and good safety profile, echinocandins have firmly taken the lead in the treatment of infections caused by Candida species. In addition, they are used in the treatment of refractory cases of invasive aspergillosis and for the prevention of invasive mycoses in selected patient populations. In this brief review, the main clinical and pharmacological characteristics of echinocandins and their positioning within the current versions of practical recommendations will be presented.

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