Update on Candida krusei, a potential multidrug-resistant pathogen

2020 ◽  
Vol 59 (1) ◽  
pp. 14-30 ◽  
Author(s):  
A T Jamiu ◽  
J Albertyn ◽  
O M Sebolai ◽  
C H Pohl
Keyword(s):  
Water Solubility ◽  
Fungal Infections ◽  
Current Knowledge ◽  
Hematologic Malignancy ◽  
Multidrug Resistant ◽  
Candida Krusei ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Intrinsic Resistance

Abstract Although Candida albicans remains the main cause of candidiasis, in recent years a significant number of infections has been attributed to non-albicans Candida (NAC) species, including Candida krusei. This epidemiological change can be partly explained by the increased resistance of NAC species to antifungal drugs. C. krusei is a diploid, dimorphic ascomycetous yeast that inhabits the mucosal membrane of healthy individuals. However, this yeast can cause life-threatening infections in immunocompromised patients, with hematologic malignancy patients and those using prolonged azole prophylaxis being at higher risk. Fungal infections are usually treated with five major classes of antifungal agents which include azoles, echinocandins, polyenes, allylamines, and nucleoside analogues. Fluconazole, an azole, is the most commonly used antifungal drug due to its low host toxicity, high water solubility, and high bioavailability. However, C. krusei possesses intrinsic resistance to this drug while also rapidly developing acquired resistance to other antifungal drugs. The mechanisms of antifungal resistance of this yeast involve the alteration and overexpression of drug target, reduction in intracellular drug concentration and development of a bypass pathway. Antifungal resistance menace coupled with the paucity of the antifungal arsenal as well as challenges involved in antifungal drug development, partly due to the eukaryotic nature of both fungi and humans, have left researchers to exploit alternative therapies. Here we briefly review our current knowledge of the biology, pathophysiology and epidemiology of a potential multidrug-resistant fungal pathogen, C. krusei, while also discussing the mechanisms of drug resistance of Candida species and alternative therapeutic approaches.

Unraveling the importance of molecules of natural origin in antifungal drug development through targeting ergosterol biosynthesis pathway

2020 ◽  
Author(s):  
Fatemehsadat Jamzivar ◽  
Masoomeh Shams-Ghahfarokhi ◽  
Mansoor Khoramizadeh ◽  
Niloufar Yousefi ◽  
Mohammadhassan Gholami-Shabani
Keyword(s):  
Drug Discovery ◽  
Fungal Infections ◽  
Current Knowledge ◽  
Fungal Growth ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Rational Drug Design ◽  
Ergosterol Biosynthesis ◽  
Biosynthesis Pathway ◽  
Natural Origin

Over the past decades, the incidence of life-threatening fungal infections has increased dramatically in particular among patients with hampered immune function. Fungal infections cause around 1.5 million deaths annually, superior to malaria and tuberculosis. With respect to high toxicity, narrow spectrum of activity and drug resistance to current antifungals, there is an urgent need to discover novel leads from molecules of natural origin especially those derived from plants and microorgan- isms for antifungal drug discovery. Among antifungal drugs introduced into the clinic, those affecting ergosterol biosynthesis are still superior to other classes and the vital role of ergosterol in fungal growth and development. This review highlights current knowledge about available antifungal agents and further issues on antifungal drug discovery from compounds of nat- ural origin which affect ergosterol biosynthesis. Special attention is made to the fungal sterol C24-methyltransferase (SMT), a crucial enzyme in ergosterol biosynthesis pathway as a novel target for rational drug design.

scholarly journals Host Defense Peptides as Templates for Antifungal Drug Development

2020 ◽  
Vol 6 (4) ◽  
pp. 241
Author(s):  
Virginia Basso ◽  
Dat Q. Tran ◽  
André J. Ouellette ◽  
Michael E. Selsted
Keyword(s):  
Host Defense ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Multidrug Resistant ◽  
Current Treatment ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Host Defense Peptides ◽  
Invasive Fungal Diseases ◽  
Defense Peptides

Current treatment for invasive fungal diseases is limited to three classes of antifungal drugs: azoles, polyenes, and echinocandins. The most recently introduced antifungal class, the echinocandins, was first approved nearly 30 years ago. The limited antifungal drug portfolio is rapidly losing its clinical utility due to the inexorable rise in the incidence of invasive fungal infections and the emergence of multidrug resistant (MDR) fungal pathogens. New antifungal therapeutic agents and novel approaches are desperately needed. Here, we detail attempts to exploit the antifungal and immunoregulatory properties of host defense peptides (HDPs) in the design and evaluation of new antifungal therapeutics and discuss historical limitations and recent advances in this quest.

Resistance to antifungal therapies

2017 ◽  
Vol 61 (1) ◽  
pp. 157-166 ◽  
Author(s):  
Rajendra Prasad ◽  
Atanu Banerjee ◽  
Abdul Haseeb Shah
Keyword(s):  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Therapeutic Strategies ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
Therapeutic Interventions ◽  
Medical Professionals ◽  
Comprehensive Understanding ◽  
Novel Targets

The evolution of antifungal resistance among fungal pathogens has rendered the limited arsenal of antifungal drugs futile. Considering the recent rise in the number of nosocomial fungal infections in immunocompromised patients, the emerging clinical multidrug resistance (MDR) has become a matter of grave concern for medical professionals. Despite advances in therapeutic interventions, it has not yet been possible to devise convincing strategies to combat antifungal resistance. Comprehensive understanding of the molecular mechanisms of antifungal resistance is essential for identification of novel targets that do not promote or delay emergence of drug resistance. The present study discusses features and limitations of the currently available antifungals, mechanisms of antifungal resistance and highlights the emerging therapeutic strategies that could be deployed to combat MDR.

scholarly journals COVID-19-Associated Candidiasis (CAC): An Underestimated Complication in the Absence of Immunological Predispositions?

2020 ◽  
Vol 6 (4) ◽  
pp. 211 ◽  
Author(s):  
Amir Arastehfar ◽  
Agostinho Carvalho ◽  
M. Hong Nguyen ◽  
Mohammad Taghi Hedayati ◽  
Mihai G. Netea ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Antibiotic Use ◽  
Multidrug Resistant ◽  
Molecular Techniques ◽  
Antifungal Drugs ◽  
Diagnostic Tools ◽  
Candida Spp ◽  
Comparative Performance ◽  
Number Of Patients ◽  
Clinical Awareness

The recent global pandemic of COVID-19 has predisposed a relatively high number of patients to acute respiratory distress syndrome (ARDS), which carries a risk of developing super-infections. Candida species are major constituents of the human mycobiome and the main cause of invasive fungal infections, with a high mortality rate. Invasive yeast infections (IYIs) are increasingly recognized as s complication of severe COVID-19. Despite the marked immune dysregulation in COVID-19, no prominent defects have been reported in immune cells that are critically required for immunity to Candida. This suggests that relevant clinical factors, including prolonged ICU stays, central venous catheters, and broad-spectrum antibiotic use, may be key factors causing COVID-19 patients to develop IYIs. Although data on the comparative performance of diagnostic tools are often lacking in COVID-19 patients, a combination of serological and molecular techniques may present a promising option for the identification of IYIs. Clinical awareness and screening are needed, as IYIs are difficult to diagnose, particularly in the setting of severe COVID-19. Echinocandins and azoles are the primary antifungal used to treat IYIs, yet the therapeutic failures exerted by multidrug-resistant Candida spp. such as C. auris and C. glabrata call for the development of new antifungal drugs with novel mechanisms of action.

scholarly journals CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Claudia Spampinato ◽  
Darío Leonardi
Keyword(s):  
Antifungal Agents ◽  
Fungal Infections ◽  
Current Knowledge ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
Diagnostic Methods ◽  
Opportunistic Pathogens ◽  
Yeast Infection ◽  
Life Threatening ◽  
Therapeutic Alternatives

The genusCandidaincludes about 200 different species, but only a few species are human opportunistic pathogens and cause infections when the host becomes debilitated or immunocompromised.Candidainfections can be superficial or invasive. Superficial infections often affect the skin or mucous membranes and can be treated successfully with topical antifungal drugs. However, invasive fungal infections are often life-threatening, probably due to inefficient diagnostic methods and inappropriate initial antifungal therapies. Here, we briefly review our current knowledge of pathogenic species of the genusCandidaand yeast infection causes and then focus on current antifungal drugs and resistance mechanisms. An overview of new therapeutic alternatives for the treatment ofCandidainfections is also provided.

scholarly journals Fungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond

2021 ◽  
Vol 17 (12) ◽  
pp. e1010073
Author(s):  
Rafael W. Bastos ◽  
Luana Rossato ◽  
Gustavo H. Goldman ◽  
Daniel A. Santos
Keyword(s):  
Fungal Pathogens ◽  
Fungal Infections ◽  
Resistance Mechanism ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Cross Resistance ◽  
Term Therapy ◽  
Prior History ◽  
Plant Materials

Fungal infections are underestimated threats that affect over 1 billion people, and Candida spp., Cryptococcus spp., and Aspergillus spp. are the 3 most fatal fungi. The treatment of these infections is performed with a limited arsenal of antifungal drugs, and the class of the azoles is the most used. Although these drugs present low toxicity for the host, there is an emergence of therapeutic failure due to azole resistance. Drug resistance normally develops in patients undergoing azole long-term therapy, when the fungus in contact with the drug can adapt and survive. Conversely, several reports have been showing that resistant isolates are also recovered from patients with no prior history of azole therapy, suggesting that other routes might be driving antifungal resistance. Intriguingly, antifungal resistance also happens in the environment since resistant strains have been isolated from plant materials, soil, decomposing matter, and compost, where important human fungal pathogens live. As the resistant fungi can be isolated from the environment, in places where agrochemicals are extensively used in agriculture and wood industry, the hypothesis that fungicides could be driving and selecting resistance mechanism in nature, before the contact of the fungus with the host, has gained more attention. The effects of fungicide exposure on fungal resistance have been extensively studied in Aspergillus fumigatus and less investigated in other human fungal pathogens. Here, we discuss not only classic and recent studies showing that environmental azole exposure selects cross-resistance to medical azoles in A. fumigatus, but also how this phenomenon affects Candida and Cryptococcus, other 2 important human fungal pathogens found in the environment. We also examine data showing that fungicide exposure can select relevant changes in the morphophysiology and virulence of those pathogens, suggesting that its effect goes beyond the cross-resistance.

scholarly journals Duplication and overexpression of the genes encoding a beta 1,3-glucan synthase confer the intrinsic resistance to echinocandin in Mucor circinelloides

2022 ◽  
Author(s):  
Soo Chan Lee ◽  
Alexis Garcia ◽  
Eun Young Huh
Keyword(s):  
Fungal Infections ◽  
Secondary Infection ◽  
Effective Means ◽  
Mucor Circinelloides ◽  
Antifungal Drugs ◽  
Solid Organ ◽  
Intrinsic Resistance ◽  
Glucan Synthase ◽  
Drug Classes ◽  
Genes Encoding

Procedures such as solid organ transplants and cancer treatments can leave many patients in an immunocompromised state resulting in an increased susceptibility to opportunistic diseases including fungal infections. Mucormycosis infections are continually emerging and pose a serious threat to immunocompromised patients. Currently there has been a sharp increase in mucormycosis cases as a secondary infection in patients battling SARS-CoV-2 infections. Mucorales fungi are notorious for presenting resistance to most antifungal drugs. The absence of effective means to treat these infections results in mortality rates approaching 100% in cases of disseminated infection. One of the most effective antifungal drug classes currently available are echinocandins. Echinocandins seem to be efficacious in treatment of many other fungal infections. Unfortunately, susceptibility testing has found that echinocandins have no to little effect on Mucorales. In this study, we found that the model Mucorales Mucor circinelloides genome carries three copies of the genes encoding for the echinocandin target protein β-(1,3)-D-glucan synthase (fksA, fksB, and fksC). Interestingly, we revealed that exposing M. circinelloides to micafungin significantly increased the expression of the fksA and fksB genes when compared to an untreated control. We further uncovered that the serine/threonine phosphatase calcineurin is responsible for the overexpression of fksA and fksB as deletion of calcineurin results in a decrease in expression of all three fks genes and a lower minimal inhibitory concentration (MIC) to micafungin. Taken together, this study demonstrates that the fks gene duplication and overexpression by calcineurin contribute to the intrinsic resistance to echinocandins in Mucor.

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 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 Photodynamic Therapy Is Effective Against Candida auris Biofilms

2021 ◽  
Vol 11 ◽  
Author(s):  
Priyanka S. Bapat ◽  
Clarissa J. Nobile
Keyword(s):  
Photodynamic Therapy ◽  
Fungal Infections ◽  
Red Light ◽  
Green Light ◽  
Multidrug Resistant ◽  
Antifungal Drug ◽  
Candida Auris ◽  
Human Fungal Pathogen ◽  
Drug Classes ◽  
Medical Need

Fungal infections are increasing in prevalence worldwide. The paucity of available antifungal drug classes, combined with the increased occurrence of multidrug resistance in fungi, has led to new clinical challenges in the treatment of fungal infections. Candida auris is a recently emerged multidrug resistant human fungal pathogen that has become a worldwide public health threat. C. auris clinical isolates are often resistant to one or more antifungal drug classes, and thus, there is a high unmet medical need for the development of new therapeutic strategies effective against C. auris. Additionally, C. auris possesses several virulence traits, including the ability to form biofilms, further contributing to its drug resistance, and complicating the treatment of C. auris infections. Here we assessed red, green, and blue visible lights alone and in combination with photosensitizing compounds for their efficacies against C. auris biofilms. We found that (1) blue light inhibited and disrupted C. auris biofilms on its own and that the addition of photosensitizing compounds improved its antibiofilm potential; (2) red light inhibited and disrupted C. auris biofilms, but only in combination with photosensitizing compounds; and (3) green light inhibited C. auris biofilms in combination with photosensitizing compounds, but had no effects on disrupting C. auris biofilms. Taken together, our findings suggest that photodynamic therapy could be an effective non-drug therapeutic strategy against multidrug resistant C. auris biofilm infections.

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