Tracking resistance to antifungal drugs for Candida spp

Abstract Candidiasis is a fungal infection caused by Candida spp. especially Candida albicans, C. glabrata, C. parapsilosis and C. tropicalis. Although the medicinal therapeutic strategies have rapidly improved, the mortality rate due to candidiasis has continuously increased. The secreted and membrane-bound virulence factors (VFs) are responsible for fungal invasion, damage and translocation through the host enterocytes besides the evasion from host immune system. VFs such as agglutinin-like sequences (Als), heat shock protein 70, phospholipases, secreted aspartyl proteinases (Sap), lipases, enolases and phytases are mostly hydrolases which degrade the enterocyte membrane components except for candidalysin, the VF acts as a peptide toxin to induce necrotic cell lysis. To date, structural studies of the VFs remain underexplored, hindering their functional analyses. Among the VFs, only secreted aspartyl proteinases and agglutinin-like sequences have their structures deposited in Protein Data Bank (PDB). Therefore, this review scrutinizes the mechanisms of these VFs by discussing the VF-deficient studies of several Candida spp. and their abilities to produce these VFs. Nonetheless, their latest reported sequential and structural analyses are discussed to impart a wider perception of the host-pathogen interactions and potential vaccine or antifungal drug targets. This review signifies that more VFs structural investigations and mining in the emerging Candida spp. are required to decipher their pathogenicity and virulence mechanisms compared to the prominent C. albicans. Lay Abstract Candida virulence factors (VFs) including mainly enzymes and proteins play vital roles in breaching the human intestinal barrier and causing deadly candidiasis. Limited VFs’ structural studies hinder deeper comprehension of their mechanisms and thus the design of vaccines and antifungal drugs against fungal infections.

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Essential oils as alternative promising anti-Candidal agents: progress and prospects

Current Pharmaceutical Design ◽

10.2174/1381612827666210914124344 ◽

2021 ◽

Vol 27 ◽

Author(s):

Awad Shala ◽

Shweta Singh ◽

Saif Hameed ◽

.M.P. Khurana

Keyword(s):

Essential Oils ◽

Antioxidant Properties ◽

Therapeutic Agents ◽

Antifungal Drugs ◽

Fungal Resistance ◽

Antifungal Compounds ◽

Candida Spp ◽

Conventional Antibiotics ◽

Opportunistic Pathogenic

: Candida albicans is one of the main agents responsible for opportunistic pathogenic infections. The progressive emergence of fungal resistance to conventional antibiotics and its side effects as well as treatment costs are considered as major limitations for antifungal drugs. It has drawn scientists' attention to search for potential substitution and therapeutic reliable alternatives for the antifungal compounds from sources like medicinal plants, which contain numerous bioactive compounds such as essential oils. Essential oils (EO) apart from having lower toxicity and better biodegradability are eco-friendly in nature as compared with conventional antibiotics. Furthermore, extracted essential oils have been reported to possess potent antimicrobial, anti-inflammatory and antioxidant properties that nominate them as natural promising candidates to combat numerous fungal ailments. Thus, determination of antifungal efficacy of essential oil-bearing plants on Candida spp. will provide miscellaneous knowledge for future clinical studies that are required for development of new formulations as alternative therapeutic agents to control the growth of Candida species. Therefore, this review summarizes the gist of major essential oils that have been investigated for their anti- Candida potential with some recommendations for further study.

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Susceptibility Pattern of Caspofungin-Coated Gold Nanoparticles against Clinically Important Candida Species

Advanced Pharmaceutical Bulletin ◽

10.34172/apb.2021.078 ◽

2020 ◽

Author(s):

Zahra Salehi ◽

Azam Fattahi ◽

Ensieh lotfali ◽

Abdolhassan Kazemi ◽

Ali Shakeri-Zadeh ◽

...

Keyword(s):

Electron Microscopy ◽

Gold Nanoparticles ◽

Cell Wall ◽

Candida Species ◽

Spherical Shape ◽

Sem Analysis ◽

Antifungal Drugs ◽

Wall Structure ◽

Candida Spp ◽

Average Size

Purpose: The present study was performed to examine whether caspofungin-coated gold nanoparticles (CAS-AuNPs) may offer the right platform for sensitivity induction in resistant isolates. Methods: For the purpose of the study, a total of 58 archived Candida species were enrolled in the research. The identification of Candida spp. was performed using polymerase chain reaction-restriction fragment length polymorphism and HWP1 gene amplification approaches. The conjugated CAS-AuNPs were synthesized and then characterized using transmission electron microscopy (TEM) and Zetasizer system to determine their morphology, size, and charge. Furthermore, the efficacy of CAS, CAS-AuNPs conjugate, and AuNPs against Candida spp. was assessed based on the Clinical and Laboratory Standards Institute M60. Finally, the interaction of CAS-AuNPs with Candida element was evaluated via scanning electron microscopy (SEM). Results: According to the TEM results, the synthesized CAS-AuNPs had a spherical shape with an average size of 20 nm. The Zeta potential of CAS-AuNPs was -38.2 mV. Statistical analyses showed that CAS-AuNPs could significantly reduce the minimum inhibitory concentration against C. albicans (P=0.0005) and non-albicans Candida (NAC) species (P<0.0001). All isolates had a MIC value of ≥ 4 µg/ml for CAS, except for C. glabrata. The results of SEM analysis confirmed the effects of AuNPs on the membrane and cell wall structure of C. globrata exposed to CAS-AuNPs, facilitating the formation of pores on the cell wall and finally cell death. Conclusion: The findings revealed that CAS-AuNPs conjugates had significant antifungal effects against Candida spp. through the degradation of the membrane and cell wall integrity. Therefore, it can be concluded that the encapsulation of antifungal drugs in combination with NPs not only diminishes side effects but also enhances the effectiveness of the medications.

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The Epidemiological Profile of Candidemia at an Indian Trauma Care Center

Journal of Laboratory Physicians ◽

10.4103/0974-2727.141506 ◽

2014 ◽

Vol 6 (02) ◽

pp. 096-101 ◽

Cited By ~ 5

Author(s):

Vibhor Tak ◽

Purva Mathur ◽

Prince Varghese ◽

Jacinta Gunjiyal ◽

Immaculata Xess ◽

...

Keyword(s):

Antifungal Susceptibility ◽

Fatal Outcome ◽

Antifungal Drugs ◽

Identification System ◽

Trauma Patients ◽

Candida Spp ◽

Tetrazolium Chloride ◽

Blood Samples ◽

Hospital Infection Control ◽

Vitek 2

ABSTRACT Purpose: Candida spp. is a common cause of bloodstream infections. Candidemia is a potentially fatal infection that needs urgent intervention to salvage the patients. Trauma patients are relatively young individuals with very few comorbidities, and the epidemiology of candidemia is relatively unknown in this vulnerable and growing population. In this study, we report the epidemiology of candidemia in a tertiary care Trauma Center of India. Materials and Methods: The study was conducted from January 2009 to July 2012. All patients from whose blood samples a Candida spp. was recovered were included in this study. A detailed history and follow up of the patients was done. The isolates of Candida were identified to the species level. The speciation was done by conventional methods, including morphology on Corn Meal Agar, color development on Triphenyl Tetrazolium Chloride Agar and CHROMagar, and germ tube tests. The VITEK 2 YST ID colorometric card, a fully automated identification system was also used. Antifungal susceptibility was performed using the VITEK 2 system. Results: A total of 212 isolates of the Candida species were recovered from blood samples of 157 patients over the study period. Candida tropicalis, 82 (39%), was the most common, followed by C. parapsilosis, 43 (20%), C. albicans, 29 (14%), C. glabrata, 24 (11%), C. rugosa, 20 (9%), C. hemulonii,; 6 (3%), C. guilliermondii, 4 (2%), C. famata, 3 (1.5%), and C. lusitaniae 1 (0.5%). Out of all the candidemia patients, 68 (43%) had a fatal outcome. Fluconazole and Amphotericin B resistance was seen in seven (3.3%) and seven (3.3%) of the isolates, respectively. Conclusion: Candidemia is a significant cause of mortality in trauma patients in our center, with C. tropicalis and C. parapsilosis being the predominant pathogens. Resistance to antifungal drugs is a matter of concern. Better hospital infection control practices and good antibiotic stewardship policies could possibly help in reducing the morbidity and mortality associated with candidemia.

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Molecules and Metabolites from Natural Products as Inhibitors of Biofilm in Candida spp. pathogens

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666191025154834 ◽

2019 ◽

Vol 19 (28) ◽

pp. 2567-2578 ◽

Cited By ~ 1

Author(s):

Rajeev K. Singla ◽

Ashok K. Dubey

Keyword(s):

Natural Products ◽

Mechanism Of Action ◽

Functional Characterization ◽

Streptococcus Thermophilus ◽

Antifungal Drugs ◽

Bioactive Molecules ◽

Review Of The Literature ◽

Candida Spp ◽

Biofilm Inhibition

Background: Biofilm is a critical virulence factor associated with the strains of Candida spp. pathogens as it confers significant resistance to the pathogen against antifungal drugs. Methods: A systematic review of the literature was undertaken by focusing on natural products, which have been reported to inhibit biofilms produced by Candida spp. The databases explored were from PubMed and Google Scholar. The abstracts and full text of the manuscripts from the literature were analyzed and included if found significant. Results: Medicinal plants from the order Lamiales, Apiales, Asterales, Myrtales, Sapindales, Acorales, Poales and Laurales were reported to inhibit the biofilms formed by Candida spp. From the microbiological sources, lactobacilli, Streptomyces chrestomyceticus and Streptococcus thermophilus B had shown the strong biofilm inhibition potential. Further, the diverse nature of the compounds from classes like terpenoids, phenylpropanoid, alkaloids, flavonoids, polyphenol, naphthoquinone and saponin was found to be significant in inhibiting the biofilm of Candida spp. Conclusion: Natural products from both plant and microbial origins have proven themselves as a goldmine for isolating the potential biofilm inhibitors with a specific or multi-locus mechanism of action. Structural and functional characterization of the bioactive molecules from active extracts should be the next line of approach along with the thorough exploration of the mechanism of action for the already identified bioactive molecules.

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

Journal of Fungi ◽

10.3390/jof6040211 ◽

2020 ◽

Vol 6 (4) ◽

pp. 211 ◽

Cited By ~ 5

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.

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Use of phylogenetical analysis to predict susceptibility of pathogenic Candida spp. to antifungal drugs

Journal of Microbiological Methods ◽

10.1016/j.mimet.2016.09.020 ◽

2016 ◽

Vol 131 ◽

pp. 51-60 ◽

Cited By ~ 1

Author(s):

Andrée F. Maheux ◽

Adnane Sellam ◽

Yves Piché ◽

Maurice Boissinot ◽

René Pelletier ◽

...

Keyword(s):

Antifungal Drugs ◽

Candida Spp

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Resistance of Candida spp. to antifungal drugs in the ICU: where are we now?

Intensive Care Medicine ◽

10.1007/s00134-014-3404-7 ◽

2014 ◽

Vol 40 (9) ◽

pp. 1241-1255 ◽

Cited By ~ 74

Author(s):

Danièle Maubon ◽

Cécile Garnaud ◽

Thierry Calandra ◽

Dominique Sanglard ◽

Muriel Cornet

Keyword(s):

Antifungal Drugs ◽

Candida Spp

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Prevalence and Fluconazole Susceptibility Profile of Candida spp. Clinical Isolates in a Brazilian Tertiary Hospital in Minas Gerais, Brazil

Anais da Academia Brasileira de Ciências ◽

10.1590/0001-3765201520140717 ◽

2015 ◽

Vol 87 (2 suppl) ◽

pp. 1349-1359 ◽

Cited By ~ 10

Author(s):

Athayde Neves-Junior ◽

Ana Carolina Cartágenes-Pinto ◽

Débora A.S. Rocha ◽

Leandro F. Reis de Sá ◽

Maria de Lourdes Junqueira ◽

...

Keyword(s):

Opportunistic Infections ◽

Fungal Infections ◽

Tertiary Hospital ◽

Antifungal Drugs ◽

Control Measures ◽

Clinical Isolates ◽

University Hospital ◽

Effective Control ◽

Candida Spp ◽

Resistance Phenotype

Candidiasis has become an important concern for clinical practice, especially with the increasing incidence of immunocompromised patients. In this scenario, the development resistance to fluconazole presents a challenge for treating these opportunistic infections. The aim of this study was to evaluate some epidemiology features of Candidainfections in a Brazilian University Hospital using data, previously unavailable. We observed that 44% of the 93 clinical isolates tested, belonged to Candida albicansspecies and 56% belonged to non-Candida albicansspecies (mainly Candida tropicalis and Candida glabrata). Most strains were isolated from urine samples where C. albicans was predominantly detected. 29 strains presented a fluconazole resistance phenotype and of these, 22 were chemosensitised by FK506, a classical inhibitor of ABC transporters related to azoles resistance. These data suggest the probable role of efflux pumps in this resistance phenotype. Our study highlights the need for developing effective control measures for fungal infections, rational use of antifungal drugs and development of new molecules able to abrogate the active transport of antifungals.

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Loss-of-function ROX1 mutations suppress the fluconazole susceptibility of upc2AΔ mutation in Candida glabrata, implicating additional positive regulators of ergosterol biosynthesis

10.1101/2021.10.07.463606 ◽

2021 ◽

Author(s):

Tomye L Ollinger ◽

Bao Vu ◽

Daniel Murante ◽

Josie Parker ◽

Lucia Simonicova ◽

...

Keyword(s):

Candida Glabrata ◽

Genetic Interaction ◽

Pathogenic Fungi ◽

Antifungal Drugs ◽

Negative Regulator ◽

Ergosterol Biosynthesis ◽

Loss Of Function ◽

Candida Spp ◽

Ergosterol Biosynthesis Inhibitors ◽

Positive Regulators

Two of the major classes of antifungal drugs in clinical use target ergosterol biosynthesis. Despite its importance, our understanding of the transcriptional regulation of ergosterol biosynthesis genes in pathogenic fungi is essentially limited to the role of hypoxia and sterol-stress induced transcription factors such as Upc2 and Upc2A as well as homologs of Sterol Response Element Binding (SREB) factors. To identify additional regulators of ergosterol biosynthesis in Candida glabrata, an important human fungal pathogen with reduced susceptibility to ergosterol biosynthesis inhibitors relative to other Candida spp., we used a serial passaging strategy to isolate suppressors of the fluconazole hypersusceptibility of a upc2AΔ deletion mutant. This led to the identification of loss of function mutants in two genes: ROX1, the homolog of a hypoxia gene transcriptional suppressor in Saccharomyces cerevisiae, and CST6, a transcription factor that is involved in the regulation of carbon dioxide response in C. glabrata. Here, we describe a detailed analysis of the genetic interaction of ROX1 and UPC2A. In the presence of fluconazole, loss of Rox1 function restores ERG11 expression to the upc2AΔ mutant and inhibits the expression of ERG3 and ERG6, leading to increased levels or ergosterol and decreased levels of the toxic sterol, 14α methyl-ergosta-8,24(28)-dien-3β, 6α-diol, relative to upc2AΔ. Our observations establish that Rox1 is a negative regulator of ERG gene biosynthesis and indicate that a least one additional positive transcriptional regulator of ERG gene biosynthesis must be present in C. glabrata.

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