scholarly journals The Neosartorya fischeri Antifungal Protein 2 (NFAP2): A New Potential Weapon against Multidrug-Resistant Candida auris Biofilms

2021 ◽  
Vol 22 (2) ◽  
pp. 771
Author(s):  
Renátó Kovács ◽  
Fruzsina Nagy ◽  
Zoltán Tóth ◽  
Lajos Forgács ◽  
Liliána Tóth ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Multidrug Resistant ◽  
Antifungal Protein ◽  
Antifungal Compound ◽  
Candida Auris ◽  
Cationic Protein ◽  
Viability Assay ◽  
Neosartorya Fischeri ◽  
Bliss Independence

Candida auris is a potential multidrug-resistant pathogen able to persist on indwelling devices as a biofilm, which serve as a source of catheter-associated infections. Neosartorya fischeri antifungal protein 2 (NFAP2) is a cysteine-rich, cationic protein with potent anti-Candida activity. We studied the in vitro activity of NFAP2 alone and in combination with fluconazole, amphotericin B, anidulafungin, caspofungin, and micafungin against C. auris biofilms. The nature of interactions was assessed utilizing the fractional inhibitory concentration index (FICI), a Bliss independence model, and LIVE/DEAD viability assay. NFAP2 exerted synergy with all tested antifungals with FICIs ranging between 0.312–0.5, 0.155–0.5, 0.037–0.375, 0.064–0.375, and 0.064–0.375 for fluconazole, amphotericin B, anidulafungin, caspofungin, and micafungin, respectively. These results were confirmed using a Bliss model, where NFAP2 produced 17.54 μM2%, 2.16 μM2%, 33.31 μM2%, 10.72 μM2%, and 111.19 μM2% cumulative synergy log volume in combination with fluconazole, amphotericin B, anidulafungin, caspofungin, and micafungin, respectively. In addition, biofilms exposed to echinocandins (32 mg/L) showed significant cell death in the presence of NFAP2 (128 mg/L). Our study shows that NFAP2 displays strong potential as a novel antifungal compound in alternative therapies to combat C. auris biofilms.

scholarly journals In Vitro Antifungal Combination of Flucytosine with Amphotericin B, Voriconazole, or Micafungin against Candida auris Shows No Antagonism

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
A. L. Bidaud ◽  
F. Botterel ◽  
A. Chowdhary ◽  
E. Dannaoui
Keyword(s):  
Amphotericin B ◽  
Inhibitory Concentration ◽  
Geometric Mean ◽  
Multidrug Resistant ◽  
Candida Auris ◽  
Content Type ◽  
Hospital Acquired Infections ◽  
Resistant Mutants ◽  
Hospital Acquired

ABSTRACT Candida auris is an emerging, multidrug-resistant pathogen responsible for invasive hospital-acquired infections. Flucytosine is an effective anti-Candida species drug, but which cannot be used as a monotherapy because of the risk of development of resistant mutants during treatment. It is, therefore, noteworthy to test possible combinations with flucytosine that may have a synergistic interaction. In this study, we determined the in vitro interaction between flucytosine and amphotericin B, micafungin, or voriconazole. These combinations have been tested against 15 C. auris isolates. The MIC ranges (geometric mean [Gmean]) of flucytosine, amphotericin B, micafungin, and voriconazole were 0.125 to 1 μg/ml (0.42 μg/ml), 0.25 to 1 μg/ml (0.66 μg/ml), 0.125 to 0.5 μg/ml (0.3 μg/ml), and 0.03 to 4 μg/ml (1.05 μg/ml), respectively. When tested in combination, indifferent interactions were mostly observed with fractional inhibitory concentration index values from 0.5 to 1, 0.31 to 1.01, and 0.5 to 1.06 for the combinations of flucytosine with amphotericin B, micafungin, and voriconazole, respectively. A synergy was observed for the strain CBS 10913 from Japan. No antagonism was observed for any combination. The combination of flucytosine with amphotericin B or micafungin may be relevant for the treatment of C. auris infections.

scholarly journals Evaluation of bisphenylthiazoles as a promising class for combating multidrug-resistant fungal infections

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0258465
Author(s):  
Mohamed Hagras ◽  
Nader S. Abutaleb ◽  
Ahmed M. Sayed ◽  
Ehab A. Salama ◽  
Mohamed N. Seleem ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Antifungal Activity ◽  
Amphotericin B ◽  
Antifungal Agent ◽  
Fungal Infections ◽  
Multidrug Resistant ◽  
Candida Auris ◽  
Conformationally Restricted ◽  
Normal Human

To minimize the intrinsic toxicity of the antibacterial agent hydrazinyloxadiazole 1, the hydrazine moiety was replaced with ethylenediamine (compound 7). This replacement generated a potent antifungal agent with no antibacterial activity. Notably, use of a 1,2-diaminocyclohexane moiety, as a conformationally-restricted isostere for ethylenediamine, potentiated the antifungal activity in both the cis and trans forms of N-(5-(2-([1,1’-biphenyl]-4-yl)-4-methylthiazol-5-yl)-1,3,4-oxadiazol-2-yl)cyclohexane-1,2-diamine (compounds 16 and 17). Both compounds 16 and 17 were void of any antibacterial activity; nonetheless, they showed equipotent antifungal activity in vitro to that of the most potent approved antifungal agent, amphotericin B. The promising antifungal effects of compounds 16 and 17 were maintained when assessed against an additional panel of 26 yeast and mold clinical isolates, including the Candida auris and C. krusei. Furthermore, compound 17 showed superior activity to amphotericin B in vitro against Candida glabrata and Cryptococcus gattii. Additionally, neither compound inhibited the normal human microbiota, and both possessed excellent safety profiles and were 16 times more tolerable than amphotericin B.

scholarly journals In Vitro Interactions of Echinocandins with Triazoles Against Multidrug-Resistant Candida auris

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S82-S82
Author(s):  
Hamid Badalii
Keyword(s):  
Amphotericin B ◽  
Antifungal Susceptibility ◽  
Multidrug Resistant ◽  
In Vivo Studies ◽  
Synergistic Activity ◽  
Candida Auris ◽  
Unsuccessful Treatment ◽  
In Vitro Interactions

Abstract Background Blood stream infections due to Candida auris are related to a high mortality rate and treatment failure attributed to resistance to fluconazole, voriconazole, amphotericin B, and caspofungin. Thus, the precise identification of agents and in vitro antifungal susceptibility testing is highly recommended. Novel therapeutic strategies, such as combination therapy, are essential for increasing the efficacy and reducing the toxicity of antifungal agents. Therefore, we investigated the in vitro combination of micafungin plus voriconazole against multidrug-resistant C. auris isolated from cases of candidemia. Methods The in vitro interactions between echinocandins and azoles were determined against ten multidrug-resistant Candida auris strains by using a microdilution checkerboard technique. Results Results revealed that MICs range for voriconazole and micafungin were 0.5–8 and 0.25–8 mg/l, respectively. The checkerboard analysis revealed that the combination of micafungin with voriconazole exhibited synergistic activity against all 10 multidrug-resistant C. auris isolates (FICI range: 0.15–0.5). Overall, no antagonistic effects were observed in this experiments. Conclusion In vitro studies have previously suggested that among azoles isavuconazole and posaconazole are more active drugs against C. auris. In addition, the majority of isolates reported are resistant to fluconazole. Remarkably, unsuccessful treatment of C. auris infections with fluconazole, voriconazole, amphotericin B, caspofungin, and anidulafungin has been already on record. Here in we demonstrates that interaction between micafungin with voriconazole exhibited synergistic activity against multidrug-resistant C. auris isolates. It seems that lower concentrations of drugs cause fewer side-effects and improve the treatment outcomes. However, in vivo studies with suitable animal models of C. auris infection is highly recommended. Disclosures All authors: No reported disclosures.

scholarly journals In-vitro antifungal resistance of Candida auris isolates from bloodstream infections, South Africa

2021 ◽  
Author(s):  
Tsidiso G. Maphanga ◽  
Serisha D. Naicker ◽  
Stanford Kwenda ◽  
Jose F. Muñoz ◽  
Erika van Schalkwyk ◽  
...  
Keyword(s):  
Amphotericin B ◽  
South African ◽  
Antifungal Agent ◽  
National Laboratory ◽  
Bloodstream Infections ◽  
Multidrug Resistant ◽  
Reference Laboratory ◽  
Candida Auris ◽  
The Common

Introduction Candida auris is a multidrug-resistant fungal pathogen endemic in South African hospitals. Materials and methods We tested bloodstream C. auris isolates that were submitted to a reference laboratory for national laboratory-based surveillance for candidaemia, 2016-2017. We confirmed species identification by phenotypic/molecular methods. We tested susceptibility to amphotericin B, anidulafungin, caspofungin, micafungin, itraconazole, posaconazole, voriconazole, fluconazole and flucytosine using broth microdilution (BMD) and Etest. We interpreted minimum inhibitory concentrations (MICs) using tentative breakpoints. We sequenced the genomes of a subset of isolates and compared to the C. auris B8441 reference strain. Results Of 400 C. auris isolates, 361 (90%) were resistant to at least one antifungal agent, 339 (85%) to fluconazole alone (MIC of ≥32 mg/L), 19 (5%) to fluconazole and amphotericin B (MIC ≥2 mg/L) and one (0.3%) to amphotericin B alone. Two (0.5%) isolates from a single patient were pan-resistant (fluconazole, amphotericin B, echinocandins). Of 93 isolates selected for whole genome sequencing, 78 clustered in clade III including the pan-resistant isolates, 13 in clade I and two in clade IV. Eighty-four of these (91%) were resistant to at least one antifungal agent; both resistant and susceptible isolates had mutations. The common substitutions identified across the different clades were VF125AL, Y132F, K177R, N335S, E343D in ERG11 ; N647T in MRR1; A651P, A657V, S195G in TAC1b; S639P in FKS1; and S58T in ERG3 genes. Conclusions Most South African C. auris isolates were resistant to azoles, though resistance to polyenes and echinocandins was less common. We observed mutations in resistance genes even in phenotypically-susceptible isolates.

scholarly journals In Vitro and In Vivo Antifungal Activity of AmBisome Compared to Conventional Amphotericin B and Fluconazole against Candida auris

2021 ◽  
Author(s):  
Janet Herrada ◽  
Ahmed Gamal ◽  
Lisa Long ◽  
Sonia P. Sanchez ◽  
Thomas S. McCormick ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Amphotericin B ◽  
Kidney Tissue ◽  
Treated Group ◽  
Untreated Group ◽  
Candida Auris ◽  
Fungal Burden ◽  
In Vivo Antifungal Activity

Antifungal activity of AmBisome against Candida auris was determined in vitro and in vivo. AmBisome showed MIC50 and MIC90 values of 1 and 2 μg/mL, respectively. Unlike conventional amphotericin B, significant in vivo efficacy was observed in the AmBisome 7.5 mg/kg -treated group in survival and reduction of kidney tissue fungal burden compared to the untreated group. Our data shows that AmBisome shows significant antifungal activity against C. auris in vitro as well as in vivo.

scholarly journals In Vitro Activity of a Novel Antifungal Compound, MYC-053, against Clinically Significant Antifungal-Resistant Strains of Candida glabrata, Candida auris, Cryptococcus neoformans, and Pneumocystis spp.

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
G. Tetz ◽  
M. Collins ◽  
D. Vikina ◽  
V. Tetz
Keyword(s):  
Cryptococcus Neoformans ◽  
Candida Glabrata ◽  
Fungal Infections ◽  
Antifungal Compound ◽  
Candida Auris ◽  
Content Type ◽  
Treatment And Prevention ◽  
Resistant Strains ◽  
Clinically Significant

ABSTRACT An urgent need exists for new antifungal compounds to treat fungal infections in immunocompromised patients. The aim of the current study was to investigate the potency of a novel antifungal compound, MYC-053, against the emerging yeast and yeast-like pathogens Candida glabrata, Candida auris, Cryptococcus neoformans, and Pneumocystis species. MYC-053 was equally effective against the susceptible control strains, clinical isolates, and resistant strains, with MICs of 0.125 to 4.0 μg/ml. Notably, unlike other antifungals such as azoles, polyenes, and echinocandins, MYC-053 was effective against Pneumocystis isolates, therefore being the only synthetic antifungal that may potentially be used against Pneumocystis spp., Candida spp., and Cryptococcus spp. MYC-053 was highly effective against preformed 48-h-old C. glabrata and C. neoformans biofilms, with minimal biofilm eradication concentrations equal to 1 to 4 times the MIC. Together, these data indicated that MYC-053 may be developed into a promising antifungal agent for the treatment and prevention of invasive fungal infections caused by yeasts and yeast-like fungi.

scholarly journals Repositionable Compounds with Antifungal Activity against Multidrug Resistant Candida auris Identified in the Medicines for Malaria Venture’s Pathogen Box

2019 ◽  
Vol 5 (4) ◽  
pp. 92 ◽  
Author(s):  
Wall ◽  
Herrera ◽  
Lopez-Ribot
Keyword(s):  
Inhibitory Activity ◽  
Multidrug Resistant ◽  
Health Care Facilities ◽  
Candida Auris ◽  
Candida Spp ◽  
Chemical Library ◽  
Growing Conditions ◽  
Multiple Strains ◽  
Susceptibility Profiles

Background. Candida auris has spread rapidly around the world as a causative agent of invasive candidiasis in health care facilities and there is an urgent need to find new options for treating this emerging, often multidrug-resistant pathogen. Methods. We screened the Pathogen Box® chemical library for inhibitors of C. auris strain 0390, both under planktonic and biofilm growing conditions. Results. The primary screen identified 12 compounds that inhibited at least 60% of biofilm formation or planktonic growth. After confirmatory dose-response assays, iodoquinol and miltefosine were selected as the two main leading repositionable compounds. Iodoquinol displayed potent in vitro inhibitory activity against planktonic C. auris but showed negligible inhibitory activity against biofilms; whereas miltefosine was able to inhibit the growth of C. auris under both planktonic and biofilm-growing conditions. Subsequent experiments confirmed their activity against nine other strains C. auris clinical isolates, irrespective of their susceptibility profiles against conventional antifungals. We extended our studies further to seven different species of Candida, also with similar findings. Conclusion. Both drugs possess broad spectrum of activity against Candida spp., including multiple strains of the emergent C. auris, and may constitute promising repositionable options for the development of novel therapeutics for the treatment of candidiasis.

scholarly journals Farnesol increases the activity of echinocandins against Candida auris biofilms

2019 ◽  
Vol 58 (3) ◽  
pp. 404-407 ◽  
Author(s):  
Fruzsina Nagy ◽  
Zoltán Tóth ◽  
Lajos Daróczi ◽  
Adrien Székely ◽  
Andrew M Borman ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Candida Auris ◽  
Independence Model ◽  
Microscope Images ◽  
Vitro Effect ◽  
Volume Range ◽  
Quorum Sensing Molecule ◽  
Bliss Independence ◽  
Scanning Electron

Abstract Candida auris biofilms exhibit decreased susceptibility to echinocandins, which is associated with poorer clinical outcomes. Farnesol is a quorum-sensing molecule enhancing the activity of antifungals; therefore, we evaluated the in vitro effect of farnesol with anidulafungin, caspofungin, or micafungin against biofilms using fractional inhibitory concentration indexes (FICI), Bliss independence model, LIVE/DEAD-assay and scanning electron microscopy. Based on mathematical models, farnesol caused synergism in eleven out of twelve cases (FICIs range 0.133-0.507; Bliss synergy volume range 70.39–204.6 μM2%). This was confirmed by microscope images of combination-exposed biofilms. Our study showed the prominent effect of farnesol with echinocandins against C. auris biofilms.

scholarly journals Ibrexafungerp: A Novel Oral Triterpenoid Antifungal in Development for the Treatment of Candida auris Infections

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 539
Author(s):  
Mahmoud Ghannoum ◽  
Maiken Cavling Arendrup ◽  
Vishnu P. Chaturvedi ◽  
Shawn R. Lockhart ◽  
Thomas S. McCormick ◽  
...  
Keyword(s):  
Antifungal Agent ◽  
Complete Response ◽  
Clinical Results ◽  
Multidrug Resistant ◽  
Candida Auris ◽  
Open Label ◽  
Candida Spp ◽  
Fungal Cell ◽  
Novel Treatments

Candida auris is an emerging multidrug-resistant fungal pathogen reported worldwide. Infections due to C. auris are usually nosocomial and associated with high rates of fluconazole resistance and mortality. Echinocandins are utilized as the first-line treatment. However, echinocandins are only available intravenously and are associated with increasingly higher rates of resistance by C. auris. Thus, a need exists for novel treatments that demonstrate potent activity against C. auris. Ibrexafungerp is a first-in-class triterpenoid antifungal agent. Similar to echinocandins, ibrexafungerp inhibits (1→3)-β-D-glucan synthase, a key component of the fungal cell wall, resulting in fungicidal activity against Candida spp. Ibrexafungerp demonstrates broad in vitro activity against various Candida spp. including C. auris and C. auris isolates with fks mutations. Minimum inhibitory concentration (MIC50 and MIC90) values in >400 C. auris isolates were 0.5 μg/mL and 1.0 μg/mL, respectively. Clinical results were reported for two patients with invasive candidiasis or candidemia due to C. auris treated during the CARES (Candidiasis Caused by Candida Auris) trial, an ongoing open-label study. These patients experienced a complete response after treatment with ibrexafungerp. Thus, ibrexafungerp represents a promising new antifungal agent for treating C. auris infections.

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