scholarly journals Drug Repurposing in Medical Mycology: Identification of Compounds as Potential Antifungals to Overcome the Emergence of Multidrug-Resistant Fungi

2021 ◽  
Vol 14 (5) ◽  
pp. 488
Author(s):  
Lucie Peyclit ◽  
Hanane Yousfi ◽  
Jean-Marc Rolain ◽  
Fadi Bittar
Keyword(s):  
Opportunistic Infections ◽  
Fungal Infections ◽  
Drug Repurposing ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Medical Community ◽  
Medical Mycology ◽  
Candida Auris

Immunodepression, whether due to HIV infection or organ transplantation, has increased human vulnerability to fungal infections. These conditions have created an optimal environment for the emergence of opportunistic infections, which is concomitant to the increase in antifungal resistance. The use of conventional antifungal drugs as azoles and polyenes can lead to clinical failure, particularly in immunocompromised individuals. Difficulties related to treating fungal infections combined with the time required to develop new drugs, require urgent consideration of other therapeutic alternatives. Drug repurposing is one of the most promising and rapid solutions that the scientific and medical community can turn to, with low costs and safety advantages. To treat life-threatening resistant fungal infections, drug repurposing has led to the consideration of well-known and potential molecules as a last-line therapy. The aim of this review is to provide a summary of current antifungal compounds and their main resistance mechanisms, following by an overview of the antifungal activity of non-traditional antimicrobial drugs. We provide their eventual mechanisms of action and the synergistic combinations that improve the activity of current antifungal treatments. Finally, we discuss drug repurposing for the main emerging multidrug resistant (MDR) fungus, including the Candida auris, Aspergillus or Cryptococcus species.

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 Evaluation of in vitro activity of manogepix against multidrug-resistant and pan-resistant Candida auris from the New York Outbreak

2020 ◽  
Author(s):  
YanChun Zhu ◽  
Shannon Kilburn ◽  
Mili Kapoor ◽  
Sudha Chaturvedi ◽  
Karen Joy Shaw ◽  
...  
Keyword(s):  
New York ◽  
Fungal Infections ◽  
Multidrug Resistant ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Candida Auris ◽  
York Metropolitan Area ◽  
Clinical Surveillance ◽  
Laboratory Surveillance

ABSTRACTAn 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 pan-resistant. 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/L; range 0.004-0.06 mg/L). The MGX epidemiological cutoff value (ECV, 99% cutoff) for the tested C. auris isolates was 0.06 mg/L. MGX was 8-32-fold more active than the echinocandins, 16-64-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 GEOMEAN values when subsets of clinical, surveillance, and environmental isolates were evaluated. The range of MGX MIC values for six C. auris pan-resistant isolates was 0.008-0.015 mg/L, and the median and mode MIC values were 0.015 mg/L, 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 Screening Repurposing Libraries for Identification of Drugs with Novel Antifungal Activity

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Gina Wall ◽  
Jose L. Lopez-Ribot
Keyword(s):  
Antifungal Activity ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Alternative Pathway ◽  
Drug Repurposing ◽  
Pathogenic Fungi ◽  
Multidrug Resistant ◽  
Modern Medicine ◽  
Antifungal Drugs ◽  
Promising Alternative

ABSTRACT Fungal organisms are ubiquitous in nature, and progress of modern medicine is creating an expanding number of severely compromised patients susceptible to a variety of opportunistic fungal infections. These infections are difficult to diagnose and treat, leading to high mortality rates. The limited antifungal arsenal, the toxicity of current antifungal drugs, the development of resistance, and the emergence of new multidrug-resistant fungi, all highlight the urgent need for new antifungal agents. Unfortunately, the development of a novel antifungal is a rather long and expensive proposition, and no new classes of antifungal agents have reached the market in the last 2 decades. Drug repurposing, or finding new indications for old drugs, represents a promising alternative pathway to drug development that is particularly appealing within the academic environment. In the last few years, there has been a growing interest in repurposing approaches in the antifungal arena, with multiple groups of investigators having performed screenings of different repurposing libraries against different pathogenic fungi in search for drugs with previously unrecognized antifungal effects. Overall, these repurposing efforts may lead to the fast deployment of drugs with novel antifungal activity, which can rapidly bring benefits to patients, while at the same time reducing health care costs.

scholarly journals 1275. Evaluation of in vitro activity of manogepix against multidrug-resistant and pan-resistant Candida auris from the New York Outbreak

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S654-S654
Author(s):  
Yan Chun Zhu ◽  
Shannon N Kilburn ◽  
Mili Kapoor ◽  
Sudha Chaturvedi ◽  
Karen J Shaw ◽  
...  
Keyword(s):  
New York ◽  
Fungal Infections ◽  
Fungal Growth ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Candida Auris ◽  
Microsoft Excel ◽  
York Metropolitan Area ◽  
Clinical Surveillance

Abstract Background An ongoing Candida auris outbreak in the New York metropolitan area is the largest recorded to date in North America. NY C. auris isolates demonstrate resistance to fluconazole and variable resistance to other antifungals. 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 in clinical development for the treatment of invasive fungal infections. Methods We evaluated the susceptibility of 200 NY C. auris isolates (2017-2020) to MGX and 10 comparators. Testing was performed using TREK frozen broth microdilution panels for FLC, VRC, ITC, ISA, POS, AFG, CAS, and MFG. MGX MICs were evaluated (CLSI M27-A3 guidelines) using a 50% reduction in fungal growth endpoint at 24 h. MICs were determined by ETEST® at 24 h for AMB and FLC. We defined pan-resistant C. auris as isolates with in vitro resistance to two or more azoles, all echinocandins, and AMB. The epidemiological cutoff values (ECVs, ECOFFs) for MGX were estimated using the Microsoft Excel spreadsheet calculator ECOFFinder. Results MGX demonstrated lower MICs than comparators (MIC50 and MIC90 0.03 mg/L; range 0.004-0.06 mg/L). MGX was 8-32-fold more active that the echinocandins, 16-64-fold more active than the azoles, and 64-fold more active than AMB. No differences were found in the MGX or comparators’ MIC50, MIC90, or GEOMEAN values when subsets of clinical, surveillance, and environmental isolates were evaluated. The range of MGX MIC values for six C. auris pan-resistant isolates was 0.008-0.015 mg/L, and the median and mode MIC values were 0.015 mg/L, demonstrating that MGX retains activity against these isolates. The MGX epidemiological cutoff value (ECV, 99% cutoff) was 0.06 mg/L. Conclusion MGX MICs were low against C. auris isolates including those with variable patterns of resistance to AMB, azoles, and echinocandins. In addition, MGX retained potent activity against six pan-resistant isolates. These data support the continued clinical evaluation of fosmanogepix for the treatment of C. auris infections, including highly resistant isolates. Disclosures Karen J. Shaw, PhD, Amplyx (Consultant)Forge Therapeutics (Consultant) Vishnu Chaturvedi, PhD, Amplyx (Grant/Research Support)

scholarly journals Fungal Diseases in the 21st Century: The Near and Far Horizons

2018 ◽  
Vol 3 (2) ◽  
pp. 183 ◽  
Author(s):  
Arturo Casadevall
Keyword(s):  
21St Century ◽  
Fungal Infections ◽  
Medical Problem ◽  
Modern Medicine ◽  
Antifungal Drugs ◽  
Fungal Diseases ◽  
New Drugs ◽  
Medical Mycology ◽  
Research Investment ◽  
Causative Agents

Fungal diseases became a major medical problem in the second half of the 20th century when advances in modern medicine together with the HIV epidemic resulted in large numbers of individuals with impaired immunity. Fungal diseases are difficult to manage because they tend to be chronic, hard to diagnose, and difficult to eradicate with antifungal drugs. This essay considers the future of medical mycology in the 21st century, extrapolating from current trends. In the near horizon, the prevalence of fungal diseases is likely to increase, as there will be more hosts with impaired immunity and drug resistance will inevitably increase after selection by antifungal drug use. We can expect progress in the development of new drugs, diagnostics, vaccines, and immunotherapies. In the far horizon, humanity may face new fungal diseases in association with climate change. Some current associations between chronic diseases and fungal infections could lead to the establishment of fungi as causative agents, which will greatly enhance their medical importance. All trends suggest that the importance of fungal diseases will increase in the 21st century, and enhanced human preparedness for this scourge will require more research investment in this group of infectious diseases.

scholarly journals Combined Antifungal Resistance and Biofilm Tolerance: the Global Threat of Candida auris

mSphere ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Ryan Kean ◽  
Gordon Ramage
Keyword(s):  
Clinical Importance ◽  
Multidrug Resistant ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
Medical Mycology ◽  
Candida Auris ◽  
Content Type ◽  
Echinocandin Resistance ◽  
Global Threat ◽  
The Impact

ABSTRACT The enigmatic yeast Candida auris has emerged over the last decade and rapidly penetrated our consciousness. The global threat from this multidrug-resistant yeast has generated a call to arms from within the medical mycology community. Over the past decade, our understanding of how this yeast has spread globally, its clinical importance, and how it tolerates and resists antifungal agents has expanded. This review highlights the clinical importance of antifungal resistance in C. auris and explores our current understanding of the mechanisms associated with azole, polyene, and echinocandin resistance. We also discuss the impact of phenotypic tolerance, with particular emphasis on biofilm-mediated resistance, and present new pipelines of antifungal drugs that promise new hope in the management of C. auris infection.

scholarly journals Amphotericin B and Other Polyenes—Discovery, Clinical Use, Mode of Action and Drug Resistance

2020 ◽  
Vol 6 (4) ◽  
pp. 321
Author(s):  
Hans Carolus ◽  
Siebe Pierson ◽  
Katrien Lagrou ◽  
Patrick Van Dijck
Keyword(s):  
Drug Resistance ◽  
Amphotericin B ◽  
Mode Of Action ◽  
Fungal Infections ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
Clinical Use ◽  
Candida Auris ◽  
Resistance Development ◽  
Resistant Species

Although polyenes were the first broad spectrum antifungal drugs on the market, after 70 years they are still the gold standard to treat a variety of fungal infections. Polyenes such as amphotericin B have a controversial image. They are the antifungal drug class with the broadest spectrum, resistance development is still relatively rare and fungicidal properties are extensive. Yet, they come with a significant host toxicity that limits their use. Relatively recently, the mode of action of polyenes has been revised, new mechanisms of drug resistance were discovered and emergent polyene resistant species such as Candida auris entered the picture. This review provides a short description of the history and clinical use of polyenes, and focusses on the ongoing debate concerning their mode of action, the diversity of resistance mechanisms discovered to date and the most recent trends in polyene resistance development.

scholarly journals The Quiet and Underappreciated Rise of Drug-Resistant Invasive Fungal Pathogens

2020 ◽  
Vol 6 (3) ◽  
pp. 138 ◽  
Author(s):  
Amir Arastehfar ◽  
Cornelia Lass-Flörl ◽  
Rocio Garcia-Rubio ◽  
Farnaz Daneshnia ◽  
Macit Ilkit ◽  
...  
Keyword(s):  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Fungal Species ◽  
Antifungal Resistance ◽  
Candida Auris ◽  
Recent Emergence ◽  
Invasive Infections

Human fungal pathogens are attributable to a significant economic burden and mortality worldwide. Antifungal treatments, although limited in number, play a pivotal role in decreasing mortality and morbidities posed by invasive fungal infections (IFIs). However, the recent emergence of multidrug-resistant Candida auris and Candida glabrata and acquiring invasive infections due to azole-resistant C. parapsilosis, C. tropicalis, and Aspergillus spp. in azole-naïve patients pose a serious health threat considering the limited number of systemic antifungals available to treat IFIs. Although advancing for major fungal pathogens, the understanding of fungal attributes contributing to antifungal resistance is just emerging for several clinically important MDR fungal pathogens. Further complicating the matter are the distinct differences in antifungal resistance mechanisms among various fungal species in which one or more mechanisms may contribute to the resistance phenotype. In this review, we attempt to summarize the burden of antifungal resistance for selected non-albicansCandida and clinically important Aspergillus species together with their phylogenetic placement on the tree of life. Moreover, we highlight the different molecular mechanisms between antifungal tolerance and resistance, and comprehensively discuss the molecular mechanisms of antifungal resistance in a species level.

Efficacy of Novel Schiff base Derivatives as Antifungal Compounds in Combination with Approved Drugs Against Candida Albicans

2019 ◽  
Vol 15 (6) ◽  
pp. 648-658 ◽  
Author(s):  
Manzoor Ahmad Malik ◽  
Shabir Ahmad Lone ◽  
Parveez Gull ◽  
Ovas Ahmad Dar ◽  
Mohmmad Younus Wani ◽  
...  
Keyword(s):  
Schiff Base ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Fungal Infections ◽  
Total Sterol ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Ergosterol Biosynthesis ◽  
Dependent Manner ◽  
Schiff Base Derivatives

Background: The increasing incidence of fungal infections, especially caused by Candida albicans, and their increasing drug resistance has drastically increased in recent years. Therefore, not only new drugs but also alternative treatment strategies are promptly required. Methods: We previously reported on the synergistic interaction of some azole and non-azole compounds with fluconazole for combination antifungal therapy. In this study, we synthesized some non-azole Schiff-base derivatives and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drugs- fluconazole (FLC) and amphotericin B (AmB) against four drug susceptible, three FLC resistant and three AmB resistant clinically isolated Candida albicans strains. To further analyze the mechanism of antifungal action of these compounds, we quantified total sterol contents in FLC-susceptible and resistant C. albicans isolates. Results: A pyrimidine ring-containing derivative SB5 showed the most potent antifungal activity against all the tested strains. After combining these compounds with FLC and AmB, 76% combinations were either synergistic or additive while as the rest of the combinations were indifferent. Interestingly, none of the combinations was antagonistic, either with FLC or AmB. Results interpreted from fractional inhibitory concentration index (FICI) and isobolograms revealed 4-10-fold reduction in MIC values for synergistic combinations. These compounds also inhibit ergosterol biosynthesis in a concentration-dependent manner, supported by the results from docking studies. Conclusion: The results of the studies conducted advocate the potential of these compounds as new antifungal drugs. However, further studies are required to understand the other mechanisms and in vivo efficacy and toxicity of these compounds.

scholarly journals 1579. Multidrug-Resistant Candida auris Isolates From New York Hospitals and Healthcare Facilities Are Susceptible to Antifungal Combinations

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S576-S577
Author(s):  
Brittany O’Brien ◽  
Sudha Chaturvedi ◽  
Vishnu Chaturvedi
Keyword(s):  
New York ◽  
Diagnostic System ◽  
Multidrug Resistant ◽  
Drug Combinations ◽  
Antifungal Drugs ◽  
Drug Resistant ◽  
Candida Auris ◽  
Current Case ◽  
Healthcare Facilities ◽  
Broth Microdilution Method

Abstract Background Candida auris outbreak continues unabated in New York with the current case counts exceeding 300 patients. We used a modification of standard CLSI broth microdilution method (BMD) if two-drug combinations are efficacious against C. auris isolates with high-resistance to fluconazole (FZ, MIC50 >256 mg/L), and variable resistance to other broad-spectrum antifungal drugs. Methods BMD plates were custom-designed and quality controlled by TREK Diagnostic System. The combination tests of 15 drug-resistant C. auris involved microtiter wells with the initial 144 two-drug combinations and their two-fold dilutions (1/2–1/32) to get 864 two-drug combinations finally. We utilized MIC100 endpoints for the drug combination readings as reported earlier for the intra- and inter-laboratory agreements obtained against Candida species and Aspergillus fumigatus (Antimicrob Agents Chemother. 2015. 59:1759–1766). We also tested minimum fungicidal concentrations (MFC). Results We tested all possible 864 two-drug antifungal combinations for nine antifungal drugs in use to yield 12,960 MIC100 readings, and MFC readings for 15 C. auris isolates. Flucytosine (FLC) at 2.0 mg/L potentiated most successful combinations with other drugs. Micafungin (MFG), Anidulafungin (AFG), Caspofungin (CAS) at individual concentrations of 0.25 mg/L combined well with FLC (2.0 mg/L) to yield MIC100 for 14, 13, and 12 of 15 C. auris isolates tested, respectively. MFG/FLC combination was also fungicidal for 4 of 15 isolates. AMB / FLC (0.25/1.0 mg/L) yielded MIC100 for 13 isolates and MFC for three test isolates. Posaconazole (POS), and Isavuconazole (ISA) and Voriconazole (VRC) also combined well with FLC (0.25/2.0 mg/L) to yield MIC100 for 12, 13, and 13 isolates, respectively. POS/FLC combination was fungicidal for three isolates. Conclusion We identified seven two drug-combinations of antifungals efficacious against drug-resistant C. auris strains. The modified BMD combination susceptibility testing could be used by the clinical laboratories to assist providers with the selection of optimal treatment for C. auris candidemia. Disclosures All authors: No reported disclosures.

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