scholarly journals Efficacy of Antifungal Monotherapies and Combinations againstAspergillus calidoustus

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
E. Glampedakis ◽  
A. T. Coste ◽  
M. Aruanno ◽  
D. Bachmann ◽  
E. Delarze ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Therapeutic Range ◽  
Potential Benefit ◽  
Galleria Mellonella ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Content Type ◽  
Content Model ◽  
Poor Outcomes

ABSTRACTInvasive fungal infections due toAspergillus calidoustuswith decreased azole susceptibility are emerging in the setting of azole prophylaxis and are associated with poor outcomes. We assessed thein vitroactivity of antifungal drugs used alone or in combinations againstA. calidoustusand found a synergistic effect between voriconazole and terbinafine at concentrations within the therapeutic range. An invertebrateGalleria mellonellamodel ofA. calidoustusinfection tended to support the potential benefit of this combination.

scholarly journals Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Cristina Lazzarini ◽  
Krupanandan Haranahalli ◽  
Robert Rieger ◽  
Hari Krishna Ananthula ◽  
Pankaj B. Desai ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Content Type ◽  
Highly Active ◽  
Pharmacokinetic Properties ◽  
Pass Through

ABSTRACTThe incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active againstCryptococcus neoformansin vitroand had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.

scholarly journals In Vitro Activity of Manogepix against Multidrug-Resistant and Panresistant Candida auris from the New York Outbreak

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
YanChun Zhu ◽  
Shannon Kilburn ◽  
Mili Kapoor ◽  
Sudha Chaturvedi ◽  
Karen Joy Shaw ◽  
...  
Keyword(s):  
New York ◽  
Fungal Infections ◽  
Geometric Mean ◽  
Multidrug Resistant ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Wild Type ◽  
Candida Auris ◽  
Content Type

ABSTRACT An ongoing Candida auris outbreak in the New York metropolitan area is the largest recorded to date in North America. Laboratory surveillance revealed NY C. auris isolates are resistant to fluconazole, with variable resistance to other currently used broad-spectrum antifungal drugs, and that several isolates are panresistant. Thus, there is an urgent need for new drugs with a novel mechanism of action to combat the resistance challenge. Manogepix (MGX) is a first-in-class agent that targets the fungal Gwt1 enzyme. The prodrug fosmanogepix is currently in phase 2 clinical development for the treatment of fungal infections. We evaluated the susceptibility of 200 New York C. auris isolates to MGX and 10 comparator drugs using CLSI methodology. MGX demonstrated lower MICs than comparators (MIC50 and MIC90, 0.03 mg/liter; range, 0.004 to 0.06 mg/liter). The local epidemiological cutoff value (ECV) for MGX indicated all C. auris isolates were within the population of wild-type (WT) strains; 0.06 mg/liter defines the upper limit of wild type (UL-WT). MGX was 8- to 32-fold more active than the echinocandins, 16- to 64-fold more active than the azoles, and 64-fold more active than amphotericin B. No differences were found in the MGX or comparators’ MIC50, MIC90, or geometric mean (GM) values when subsets of clinical, surveillance, and environmental isolates were evaluated. The range of MGX MIC values for six C. auris panresistant isolates was 0.008 to 0.015 mg/liter, and the median and mode MIC values were 0.015 mg/liter, demonstrating that MGX retains activity against these isolates. These data support further clinical evaluation of fosmanogepix for the treatment of C. auris infections, including highly resistant isolates.

scholarly journals Chitosan Ameliorates Candida auris Virulence in a Galleria mellonella Infection Model

2020 ◽  
Vol 64 (8) ◽  
Author(s):  
Laís Salomão Arias ◽  
Mark C. Butcher ◽  
Bryn Short ◽  
Emily McKloud ◽  
Chris Delaney ◽  
...  
Keyword(s):  
Galleria Mellonella ◽  
Survival Rates ◽  
Health Care Facilities ◽  
Antifungal Drugs ◽  
Infection Model ◽  
Candida Auris ◽  
Gene Expression Response ◽  
Content Type

ABSTRACT Candida auris has emerged as a multidrug-resistant nosocomial pathogen over the last decade. Outbreaks of the organism in health care facilities have resulted in life-threatening invasive candidiasis in over 40 countries worldwide. Resistance by C. auris to conventional antifungal drugs such as fluconazole and amphotericin B means that alternative therapeutics must be explored. As such, this study served to investigate the efficacy of a naturally derived polysaccharide called chitosan against aggregative (Agg) and nonaggregative (non-Agg) isolates of C. auris in vitro and in vivo. In vitro results indicated that chitosan was effective against planktonic and sessile forms of Agg and non-Agg C. auris. In a Galleria mellonella model to assess C. auris virulence, chitosan treatment was shown to ameliorate killing effects of both C. auris phenotypes (NCPF 8973 and NCPF 8978, respectively) in vivo. Specifically, chitosan reduced the fungal load and increased survival rates of infected Galleria, while treatment alone was nontoxic to the larvae. Finally, chitosan treatment appeared to induce a stress-like gene expression response in NCPF 8973 in the larvae likely arising from a protective response by the organism to resist antifungal activity of the compound. Taken together, results from this study demonstrate that naturally derived compounds such as chitosan may be useful alternatives to conventional antifungals against C. auris.

scholarly journals In Vitro and In Vivo Study on the Synergistic Effect of Minocycline and Azoles against Pathogenic Fungi

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Lujuan Gao ◽  
Yi Sun ◽  
Mingzhu Yuan ◽  
Ming Li ◽  
Tongxiang Zeng
Keyword(s):  
Galleria Mellonella ◽  
Pathogenic Fungi ◽  
Content Type ◽  
Content Model ◽  
Fold Reduction ◽  
Survival Assay ◽  
Synergistic Combinations ◽  
High Mics

ABSTRACT In vitro and in vivo interactions of minocycline and azoles, including itraconazole, voriconazole, and posaconazole, against filamentous pathogenic fungi were investigated. A total of 56 clinical isolates were studied in vitro via broth microdilution checkerboard technique, including 20 strains of Aspergillus fumigatus, 7 strains of Aspergillus flavus, 16 strains of Exophiala dermatitidis, 10 strains of Fusarium solani, and 3 strain s of Fusarium oxysporum. The results revealed that minocycline did not exhibit any significant antifungal activity against any of the tested strains. However, favorable synergy of minocycline with itraconazole, voriconazole, or posaconazole was observed against 34 (61%), 28 (50%), and 38 (68%) isolates, respectively, including azole-resistant A. fumigatus and Fusarium spp. with inherently high MICs of azoles. Synergistic combinations resulted in 4-fold to 16-fold reduction of effective MICs of minocycline and azoles. No antagonism was observed. In vivo effects of minocycline-azole combinations were evaluated by survival assay in a Galleria mellonella model infected with E. dermatitidis strain BMU00034; F. solani strain FS9; and A. fumigatus strains AF293, AFR1, and AFR2. Minocycline acted synergistically with azoles and significantly increased larvae survival in all isolates (P < 0.001), including azole-resistant A. fumigatus and azole-inactive Fusarium spp. In conclusion, the results suggested that minocycline combined with azoles may help to enhance the antifungal susceptibilities of azoles against pathogenic fungi and had the potential to overcome azole resistance issues.

scholarly journals Acetylcholine Protects against Candida albicans Infection by Inhibiting Biofilm Formation and Promoting Hemocyte Function in a Galleria mellonella Infection Model

2015 ◽  
Vol 14 (8) ◽  
pp. 834-844 ◽  
Author(s):  
Ranjith Rajendran ◽  
Elisa Borghi ◽  
Monica Falleni ◽  
Federica Perdoni ◽  
Delfina Tosi ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Biofilm Formation ◽  
Galleria Mellonella ◽  
Inflammatory Responses ◽  
Fungal Infections ◽  
Infection Model ◽  
Content Type

ABSTRACT Both neuronal acetylcholine and nonneuronal acetylcholine have been demonstrated to modulate inflammatory responses. Studies investigating the role of acetylcholine in the pathogenesis of bacterial infections have revealed contradictory findings with regard to disease outcome. At present, the role of acetylcholine in the pathogenesis of fungal infections is unknown. Therefore, the aim of this study was to determine whether acetylcholine plays a role in fungal biofilm formation and the pathogenesis of Candida albicans infection. The effect of acetylcholine on C. albicans biofilm formation and metabolism in vitro was assessed using a crystal violet assay and phenotypic microarray analysis. Its effect on the outcome of a C. albicans infection, fungal burden, and biofilm formation were investigated in vivo using a Galleria mellonella infection model. In addition, its effect on modulation of host immunity to C. albicans infection was also determined in vivo using hemocyte counts, cytospin analysis, larval histology, lysozyme assays, hemolytic assays, and real-time PCR. Acetylcholine was shown to have the ability to inhibit C. albicans biofilm formation in vitro and in vivo . In addition, acetylcholine protected G. mellonella larvae from C. albicans infection mortality. The in vivo protection occurred through acetylcholine enhancing the function of hemocytes while at the same time inhibiting C. albicans biofilm formation. Furthermore, acetylcholine also inhibited inflammation-induced damage to internal organs. This is the first demonstration of a role for acetylcholine in protection against fungal infections, in addition to being the first report that this molecule can inhibit C. albicans biofilm formation. Therefore, acetylcholine has the capacity to modulate complex host-fungal interactions and plays a role in dictating the pathogenesis of fungal infections.

scholarly journals Galleria mellonella for the Evaluation of Antifungal Efficacy against Medically Important Fungi, a Narrative Review

2020 ◽  
Vol 8 (3) ◽  
pp. 390 ◽  
Author(s):  
Sana Jemel ◽  
Jacques Guillot ◽  
Kalthoum Kallel ◽  
Françoise Botterel ◽  
Eric Dannaoui
Keyword(s):  
Fungal Pathogens ◽  
Galleria Mellonella ◽  
Fungal Infections ◽  
Antifungal Susceptibility ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Development Of Resistance ◽  
Antifungal Efficacy

The treatment of invasive fungal infections remains challenging and the emergence of new fungal pathogens as well as the development of resistance to the main antifungal drugs highlight the need for novel therapeutic strategies. Although in vitro antifungal susceptibility testing has come of age, the proper evaluation of therapeutic efficacy of current or new antifungals is dependent on the use of animal models. Mammalian models, particularly using rodents, are the cornerstone for evaluation of antifungal efficacy, but are limited by increased costs and ethical considerations. To circumvent these limitations, alternative invertebrate models, such as Galleria mellonella, have been developed. Larvae of G. mellonella have been widely used for testing virulence of fungi and more recently have proven useful for evaluation of antifungal efficacy. This model is suitable for infection by different fungal pathogens including yeasts (Candida, Cryptococcus, Trichosporon) and filamentous fungi (Aspergillus, Mucorales). Antifungal efficacy may be easily estimated by fungal burden or mortality rate in infected and treated larvae. The aim of the present review is to summarize the actual data about the use of G. mellonella for testing the in vivo efficacy of licensed antifungal drugs, new drugs, and combination therapies.

scholarly journals Nanoemulsion as an Effective Treatment against Human-Pathogenic Fungi

mSphere ◽  
2019 ◽  
Vol 4 (6) ◽  
Author(s):  
Alexis Garcia ◽  
Yong Yi Fan ◽  
Sandeep Vellanki ◽  
Eun Young Huh ◽  
DiFernando Vanegas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Antifungal Drugs ◽  
Solid Organ ◽  
Therapeutic Approaches ◽  
Content Type ◽  
New Therapeutic Approaches ◽  
Development Of Resistance

ABSTRACT Infections triggered by pathogenic fungi cause a serious threat to the public health care system. In particular, an increase of antifungal drug-resistant fungi has resulted in difficulty in treatment. A limited variety of antifungal drugs available to treat patients has left us in a situation where we need to develop new therapeutic approaches that are less prone to development of resistance by pathogenic fungi. In this study, we demonstrate the efficacy of the nanoemulsion NB-201, which utilizes the surfactant benzalkonium chloride, against human-pathogenic fungi. We found that NB-201 exhibited in vitro activity against Candida albicans, including both planktonic growth and biofilms. Furthermore, treatments with NB-201 significantly reduced the fungal burden at the infection site and presented an enhanced healing process after subcutaneous infections by multidrug-resistant C. albicans in a murine host system. NB-201 also exhibited in vitro growth inhibition activity against other fungal pathogens, including Cryptococcus spp., Aspergillus fumigatus, and Mucorales. Due to the nature of the activity of this nanoemulsion, there is a minimized chance of drug resistance developing, presenting a novel treatment to control fungal wound or skin infections. IMPORTANCE Advances in medicine have resulted in the discovery and implementation of treatments for human disease. While these recent advances have been beneficial, procedures such as solid-organ transplants and cancer treatments have left many patients in an immunocompromised state. Furthermore, the emergence of immunocompromising diseases such as HIV/AIDS or other immunosuppressive medical conditions have opened an opportunity for fungal infections to afflict patients globally. The development of drug resistance in human-pathogenic fungi and the limited array of antifungal drugs has left us in a scenario where we need to develop new therapeutic approaches to treat fungal infections that are less prone to the development of resistance by pathogenic fungi. The significance of our work lies in utilizing a novel nanoemulsion formulation to treat topical fungal infections while minimizing risks of drug resistance development.

Potential of Nanoparticles in Combating Candida Infections

2019 ◽  
Vol 16 (5) ◽  
pp. 478-491 ◽  
Author(s):  
Faizan Abul Qais ◽  
Mohd Sajjad Ahmad Khan ◽  
Iqbal Ahmad ◽  
Abdullah Safar Althubiani
Keyword(s):  
Targeted Delivery ◽  
Recent Progress ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Fold Increase ◽  
Antifungal Drugs ◽  
Low Toxicity ◽  
Candida Infections ◽  
Made In

Aims: The aim of this review is to survey the recent progress made in developing the nanoparticles as antifungal agents especially the nano-based formulations being exploited for the management of Candida infections. Discussion: In the last few decades, there has been many-fold increase in fungal infections including candidiasis due to the increased number of immunocompromised patients worldwide. The efficacy of available antifungal drugs is limited due to its associated toxicity and drug resistance in clinical strains. The recent advancements in nanobiotechnology have opened a new hope for the development of novel formulations with enhanced therapeutic efficacy, improved drug delivery and low toxicity. Conclusion: Metal nanoparticles have shown to possess promising in vitro antifungal activities and could be effectively used for enhanced and targeted delivery of conventionally used drugs. The synergistic interaction between nanoparticles and various antifungal agents have also been reported with enhanced antifungal activity.

scholarly journals Biological Impact of a Large-Scale Genomic Inversion That Grossly Disrupts the Relative Positions of the Origin and Terminus Loci of theStreptococcus pyogenesChromosome

2019 ◽  
Vol 201 (17) ◽  
Author(s):  
Dragutin J. Savic ◽  
Scott V. Nguyen ◽  
Kimberly McCullor ◽  
W. Michael McShan
Keyword(s):  
Dna Sequences ◽  
Parental Strain ◽  
Large Scale ◽  
Galleria Mellonella ◽  
Acute Infection ◽  
Relative Length ◽  
Published Data ◽  
Rich Medium ◽  
Content Type

ABSTRACTA large-scale genomic inversion encompassing 0.79 Mb of the 1.816-Mb-longStreptococcus pyogenesserotype M49 strain NZ131 chromosome spontaneously occurs in a minor subpopulation of cells, and in this report genetic selection was used to obtain a stable lineage with this chromosomal rearrangement. This inversion, which drastically displaces theorisite relative to the terminus, changes the relative length of the replication arms so that one replichore is approximately 0.41 Mb while the other is about 1.40 Mb in length. Genomic reversion to the original chromosome constellation is not observed in PCR-monitored analyses after 180 generations of growth in rich medium. Compared to the parental strain, the inversion surprisingly demonstrates a nearly identical growth pattern in the first phase of the exponential phase, but differences do occur when resources in the medium become limited. When cultured separately in rich medium during prolonged stationary phase or in an experimental acute infection animal model (Galleria mellonella), the parental strain and the invertant have equivalent survival rates. However, when they are coincubated together, bothin vitroandin vivo, the survival of the invertant declines relative to the level for the parental strain. The accompanying aspect of the study suggests that inversions taking place nearoriCalways happen to secure the linkage oforiCto DNA sequences responsible for chromosome partition. The biological relevance of large-scale inversions is also discussed.IMPORTANCEBased on our previous work, we created to our knowledge the largest asymmetric inversion, covering 43.5% of theS. pyogenesgenome. In spite of a drastic replacement of origin of replication and the unbalanced size of replichores (1.4 Mb versus 0.41 Mb), the invertant, when not challenged with its progenitor, showed impressive vitality for growthin vitroand in pathogenesis assays. The mutant supports the existing idea that slightly deleterious mutations can provide the setting for secondary adaptive changes. Furthermore, comparative analysis of the mutant with previously published data strongly indicates that even large genomic rearrangements survive provided that the integrity of theoriCand the chromosome partition cluster is preserved.

scholarly journals In VitroActivities of Nine Antifungal Drugs against 81 Phialophora and Cyphellophora Isolates

2012 ◽  
Vol 56 (11) ◽  
pp. 6044-6047 ◽  
Author(s):  
Peiying Feng ◽  
M. Javad Najafzadeh ◽  
Jiufeng Sun ◽  
Sarah Ahmed ◽  
Liyan Xi ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Antifungal Drugs ◽  
Content Type

ABSTRACTCyphellophora guyanensis(n= 15), otherCyphellophoraspecies (n= 11),Phialophora europaea(n= 43), and otherPhialophoraspecies (n= 12) were testedin vitroagainst nine antifungal drugs. The MIC90s across all of the strains (n= 81) were, in increasing order, as follows: posaconazole, 0.063 μg/ml; itraconazole, 0.5 μg/ml; voriconazole, 1 μg/ml; micafungin, 1 μg/ml; terbinafine, 2 μg/ml; isavuconazole, 4 μg/ml; caspofungin, 4 μg/ml; fluconazole, 8 μg/ml; amphotericin B, 16 μg/ml.

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