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

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.

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

Antibiotics ◽

10.3390/antibiotics9090539 ◽

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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In Vitro Evaluation of Antifungal Drug Combinations against Multidrug-Resistant Candida auris Isolates from New York Outbreak

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02195-19 ◽

2020 ◽

Vol 64 (4) ◽

Cited By ~ 6

Author(s):

Brittany O’Brien ◽

Sudha Chaturvedi ◽

Vishnu Chaturvedi

Keyword(s):

New York ◽

Drug Combination ◽

Multidrug Resistant ◽

Drug Combinations ◽

Health Care Facilities ◽

Antifungal Drugs ◽

Candida Auris ◽

Pathogenic Yeast ◽

Content Type

ABSTRACT Since 2016, New York hospitals and health care facilities have faced an unprecedented outbreak of the pathogenic yeast Candida auris. We tested over 1,000 C. auris isolates from affected facilities and found high resistance to fluconazole (MIC > 256 mg/liter) and variable resistance to other antifungal drugs. Therefore, we tested if two-drug combinations are effective in vitro against multidrug-resistant C. auris. Broth microdilution antifungal combination plates were custom manufactured by TREK Diagnostic System. We used 100% inhibition endpoints for the drug combination as reported earlier for the intra- and interlaboratory agreements against Candida species. The results were derived from 12,960 readings, for 15 C. auris isolates tested against 864 two-drug antifungal combinations for nine antifungal drugs. Flucytosine (5FC) at 1.0 mg/liter potentiated the most combinations. For nine C. auris isolates resistant to amphotericin B (AMB; MIC ≥ 2.0 mg/liter), AMB-5FC (0.25/1.0 mg/liter) yielded 100% inhibition. Six C. auris isolates resistant to three echinocandins (anidulafungin [AFG], MIC ≥ 4.0 mg/liter; caspofungin [CAS], MIC ≥ 2.0 mg/liter; and micafungin [MFG], MIC ≥ 4.0 mg/liter) were 100% inhibited by AFG-5FC and CAS-5FC (0.0078/1 mg/liter) and MFG-5FC (0.12/1 mg/liter). None of the combinations were effective for C. auris 18-1 and 18-13 (fluconazole [FLC] > 256 mg/liter, 5FC > 32 mg/liter) except MFG-5FC (0.1/0.06 mg/liter). Thirteen isolates with a high voriconazole (VRC) MIC (>2 mg/liter) were 100% inhibited by the VRC-5FC (0.015/1 mg/liter). The simplified two-drug combination susceptibility test format would permit laboratories to provide clinicians and public health experts with additional data to manage multidrug-resistant C. auris.

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Two Candida auris Cases in Germany with No Recent Contact to Foreign Healthcare—Epidemiological and Microbiological Investigations

Journal of Fungi ◽

10.3390/jof7050380 ◽

2021 ◽

Vol 7 (5) ◽

pp. 380

Author(s):

Joerg Steinmann ◽

Thomas Schrauzer ◽

Lisa Kirchhoff ◽

Jacques F. Meis ◽

Peter-Michael Rath

Keyword(s):

South Asian ◽

Multidrug Resistant ◽

Health Care Facilities ◽

Candida Auris ◽

Contact Precautions ◽

Asian Clade ◽

Care Facilities ◽

Long Time ◽

European Health ◽

Healthcare Associated

Candida auris has become a global fungal public health threat. This multidrug-resistant yeast is associated with nosocomial intra- and interhospital transmissions causing healthcare-associated infections. Here, we report on two C. auris cases from Germany. The two patients stayed in Germany for a long time before C. auris was detected during their hospitalization. The patients were isolated in single rooms with contact precautions. No nosocomial transmissions were detected within the hospital. Both C. auris isolates exhibited high minimum inhibitory concentrations (MICs) of fluconazole and one isolate additionally high MICs against the echinocandins. Microsatellite genotyping showed that both strains belong to the South Asian clade. These two cases are examples for appropriate in-hospital care and infection control without further nosocomial spread. Awareness for this emerging, multidrug-resistant pathogen is justified and systematic surveillance in European health care facilities should be performed.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01393-19 ◽

2019 ◽

Vol 63 (12) ◽

Cited By ~ 8

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.

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In Vitro Interactions of Echinocandins with Triazoles against Multidrug-Resistant Candida auris

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01056-17 ◽

2017 ◽

Vol 61 (11) ◽

Cited By ~ 39

Author(s):

Hamed Fakhim ◽

Anuradha Chowdhary ◽

Anupam Prakash ◽

Afsane Vaezi ◽

Eric Dannaoui ◽

...

Keyword(s):

Concentration Index ◽

Inhibitory Concentration ◽

Multidrug Resistant ◽

Fractional Inhibitory Concentration ◽

Candida Auris ◽

Fractional Inhibitory Concentration Index ◽

Synergistic Interactions ◽

In Vitro Interactions

ABSTRACT We determined the in vitro interactions between echinocandins and azoles against 10 multidrug-resistant Candida auris strains by use of a microdilution checkerboard technique. Our results suggest synergistic interactions between micafungin and voriconazole with fractional inhibitory concentration index (FICI) values of 0.15 to 0.5, and we observed indifferent interactions when micafungin was combined with fluconazole (FICI, 0.62 to 1.5). Combinations of caspofungin with fluconazole or voriconazole exhibited indifferent interactions. No antagonism was observed for any combination.

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

PLoS ONE ◽

10.1371/journal.pone.0258465 ◽

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.

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Discovery of (3-Benzyl-5-hydroxyphenyl)carbamates as New Antitubercular Agents with Potent In Vitro and In Vivo Efficacy

Molecules ◽

10.3390/molecules24102021 ◽

2019 ◽

Vol 24 (10) ◽

pp. 2021 ◽

Cited By ~ 2

Author(s):

Ya-Juan Cheng ◽

Zhi-Yong Liu ◽

Hua-Ju Liang ◽

Cui-Ting Fang ◽

Niu-Niu Zhang ◽

...

Keyword(s):

Oral Administration ◽

Inhibitory Activity ◽

Multidrug Resistant ◽

Infection Model ◽

Antitubercular Agents ◽

In Vivo Efficacy ◽

Mouse Infection Model ◽

Good Potential

A series of 3-amino-5-benzylphenol derivatives were designed and synthesized. Among them, (3-benzyl-5-hydroxyphenyl)carbamates were found to exert good inhibitory activity against M. tuberculosis H37Ra, H37Rv and clinically isolated multidrug-resistant M. tuberculosis strains (MIC = 0.625–6.25 μg/mL). The privileged compounds 3i and 3l showed moderate cytotoxicity against cell line A549. Compound 3l also exhibited potent in vivo inhibitory activity on a mouse infection model via the oral administration. The results demonstrated 3-hydroxyphenylcarbamates as a class of new antitubercular agents with good potential.

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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.026 ◽

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.

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Survival, Persistence, and Isolation of the Emerging Multidrug-Resistant Pathogenic Yeast Candida auris on a Plastic Health Care Surface

Journal of Clinical Microbiology ◽

10.1128/jcm.00921-17 ◽

2017 ◽

Vol 55 (10) ◽

pp. 2996-3005 ◽

Cited By ~ 160

Author(s):

Rory M. Welsh ◽

Meghan L. Bentz ◽

Alicia Shams ◽

Hollis Houston ◽

Amanda Lyons ◽

...

Keyword(s):

Health Care ◽

Multidrug Resistant ◽

Health Care Facilities ◽

Candida Auris ◽

Pathogenic Yeast ◽

Content Type ◽

Health Care Settings ◽

Care Facilities ◽

Enrichment Protocol ◽

Plastic Surfaces

ABSTRACTThe emerging multidrug-resistant pathogenic yeastCandida aurisrepresents a serious threat to global health. Unlike most otherCandidaspecies, this organism appears to be commonly transmitted within health care facilities and causes health care-associated outbreaks. To better understand the epidemiology of this emerging pathogen, we investigated the ability ofC. auristo persist on plastic surfaces common in health care settings compared with that ofCandida parapsilosis, a species known to colonize the skin and plastics. Specifically, we compiled comparative and quantitative data essential to understanding the vehicles of spread and the ability of both species to survive and persist on plastic surfaces under controlled conditions (25°C and 57% relative humidity), such as those found in health care settings. When a test suspension of 104cells was applied and dried on plastic surfaces,C. aurisremained viable for at least 14 days andC. parapsilosisfor at least 28 days, as measured by CFU. However, survival measured by esterase activity was higher forC. auristhanC. parapsilosisthroughout the 28-day study. Given the notable length of timeCandidaspecies survive and persist outside their host, we developed methods to more effectively cultureC. aurisfrom patients and their environment. Using our enrichment protocol, public health laboratories and researchers can now readily isolateC. aurisfrom complex microbial communities (such as patient skin, nasopharynx, and stool) as well as environmental biofilms, in order to better understand and preventC. auriscolonization and transmission.

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Ex VivoActivity of Histone Deacetylase Inhibitors against Multidrug-Resistant Clinical Isolates ofPlasmodium falciparumandP. vivax

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01220-10 ◽

2010 ◽

Vol 55 (3) ◽

pp. 961-966 ◽

Cited By ~ 33

Author(s):

Jutta Marfurt ◽

Ferryanto Chalfein ◽

Pak Prayoga ◽

Frans Wabiser ◽

Enny Kenangalem ◽

...

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Ex Vivo ◽

Hdac Inhibitors ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Antimalarial Therapy ◽

Susceptibility Profiles ◽

Antimalarial Compounds

ABSTRACTHistone acetylation plays an important role in regulating gene transcription and silencing inPlasmodium falciparum. Histone deacetylase (HDAC) inhibitors, particularly those of the hydroxamate class, have been shown to have potentin vitroactivity against drug-resistant and -sensitive laboratory strains ofP. falciparum, raising their potential as a new class of antimalarial compounds. In the current study, stage-specificex vivosusceptibility profiles of representative hydroxamate-based HDAC inhibitors suberoylanilide hydroxamic acid (SAHA), 2-ASA-9, and 2-ASA-14 (2-ASA-9 and 2-ASA-14 are 2-aminosuberic acid-based HDAC inhibitors) were assessed in multidrug-resistant clinical isolates ofP. falciparum(n= 24) andP. vivax(n= 25) from Papua, Indonesia, using a modified schizont maturation assay. Submicromolar concentrations of SAHA, 2-ASA-9, and 2-ASA-14 inhibited the growth of bothP. falciparum(median 50% inhibitory concentrations [IC50s] of 310, 533, and 266 nM) andP. vivax(median IC50s of 170, 503, and 278 nM). Inverse correlation patterns between HDAC inhibitors and chloroquine forP. falciparumand mefloquine forP. vivaxindicate species-specific susceptibility profiles for HDAC inhibitors. These HDAC inhibitors were also found to be potentex vivoagainstP.vivaxschizont maturation, comparable to that inP. falciparum, suggesting that HDAC inhibitors may be promising candidates for antimalarial therapy in geographical locations where both species are endemic. Further studies optimizing the selectivity andin vivoefficacy of HDAC inhibitors inPlasmodiumspp. and defining drug interaction with common antimalarial compounds are warranted to investigate the role of HDAC inhibitors in antimalarial therapy.

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