Drug repurposing against Candida auris: A systematic review.

Candida auris is a drug-resistant pathogen with several reported outbreaks. The treatment of C. auris infections is difficult due to a limited number of available antifungal drugs. Thus, finding alternative drugs through repurposing approaches would be clinically beneficial. A systematic search in PubMed, Scopus and Web of Science databases, as well as Google Scholar up to 1 November 2021, was conducted to find all articles with data regarding the antifungal activity of non-antifungal drugs against the planktonic and biofilm forms of C. auris. During database and hand searching, 290 articles were found, of which 13 were eligible for inclusion in the present study. Planktonic and biofilm forms have been studied in 11 and 8 articles (with both forms examined in 6 articles), respectively. In total, 22 and 12 drugs/compounds have been reported as repositionable against planktonic and biofilm forms of C. auris, respectively. Antiparasitic drugs, with the dominance of miltefosine, were the most common repurposed drugs against both forms of C. auris, followed by anticancer drugs (e.g. alexidine dihydrochloride) against the planktonic form and anti-inflammatory drugs (e.g. ebselen) against the biofilm form of the fungus. A collection of other drugs from various classes have also shown promising activity against C. auris. Following drug repurposing approaches, a number of drugs/compounds from various classes have been found to inhibit the planktonic and biofilm forms of C. auris. Accordingly, drug repurposing is an encouraging approach for discovering potential alternatives to conventional antifungal agents to combat drug resistance in fungi, especially C. auris.

Vulvovaginal candidiasis: An overview of mycological, clinical, and immunological aspects.

AIM: To provide an overview of clinical, immunological, and mycological aspects of vulvovaginal candidiasis (VVC). METHODS: A literature search was conducted to find relevant articles about different aspects of VVC. Related data from retrieved articles were summarized in different headings. RESULTS: VVC has a global distribution and Candida albicans is the leading cause of infection except for specific patient groups like postmenopausal, diabetic, or immunocompromised women. VVC has a range of clinical presentations, accordingly, its diagnosis should be based on clinical examination coupled with laboratory investigations. The best therapeutic regimen depends on the patient's conditions and the causative agent. Moreover, factors like drug resistance of the causative agents and different mutations in the immunity-related genes could affect the treatment outcome. CONCLUSION: As a globally distributed disease, VVC needs further attention, especially in areas related to the treatment failure and recurrence of the disease.

New weapons to fight a new enemy: A systematic review of drug combinations against the drug-resistant fungus Candida auris.

Candida auris is an emerging and drug-resistant pathogen. Drug combination is a promising approach against such pathogens. This study was conducted to provide an overview of all the studied drug combinations against C. auris. Relevant articles reporting results of any drug/non-drug combinations against C. auris were found by a systematic search in PubMed, Scopus and Web of Science (ISI), and in Google Scholar up to 1 October 2020. From 187 articles retrieved in the primary search, 23 met the inclusion criteria. In total, 124 different combinations including antifungal with antifungal (45), antifungal with other antimicrobials (11), antifungal with non-antimicrobials (32), antifungal with natural compounds (25) and between natural compounds (11) have been reported. Complete or partial synergistic effects have been reported for 3 out of 45 (6.67%) combinations of two antifungal agents, 8 out of 11 (72.73%) combinations involving antifungal agents and antimicrobials, 15 out of 32 (46.88%) of combinations between antifungal agents with non-antimicrobials, 16 out of 25 (64%) of combinations involving antifungal agents and natural compounds, and 3 out of 11 (22.27%) of combinations involving multiple natural compounds. Antagonistic interactions have been reported for 1 out of 32 (3.13%) and 8 out of 25 (32%) of combinations between antifungal drugs with non-antimicrobials and with natural compounds, respectively. Different drugs/compounds could potentiate the activity of antifungal drugs using this approach. However, despite the availability of this promising initial data, many more studies will be required to elucidate whether favourable interactions observed in vitro might translate into tangible clinical benefits.

MGL_3741 gene contributes to pathogenicity of Malassezia globosa in pityriasis versicolor.

Dihydroxyacid dehydratase (DHAD) is a key enzyme in biosynthetic pathway of isoleucine and valine. This pathway is absent in human but exists in various organisms such as fungi. Using RNA-seq analysis in this study, we identified MGL_3741gene which encodes DHAD protein in Malassezia globosa (M. globosa). Furthermore, we found that mentioned gene is homologous to the Ustilago maydis, Saccharomyces cerevisiae, Aspergillus flavus, and Aspergillus fumigatus ILV3P. For understanding the probable role of this gene in pathogenicity of M. globosa, we applied Real-time PCR to investigate the differentially expressed of the MGL_3741 gene in healthy and pathogenic states. Our results indicate a significant difference between two mentioned stats. These results revealed that ILV3-like gene in M. globosa can be related to the pathogenicity of this yeast.

Candida auris and COVID-19: A health threatening combination.

Since its first emergence in December 2019, due to its fast distribution throughout the world, SARS-COV-2 become a global concern. With the extremely increased number of hospitalized patients, this situation provided a potential basis for the transmission of nosocomial infections. Candida auris is a multidrug-resistant pathogen with improved transmission dynamics and resistance traits. During the worldwide spread of COVID-19, cases or outbreaks of C. auris colonization or infection have been reported. Resistance to antifungal drugs has been observed in the causative agents of the majority of such cases. The focus in this review is on COVID-19-associated C. auris infections (case studies/outbreaks) and the pandemic's potential effect on antifungal drug resistance.

Unveiling the structure of GPI-anchored protein of Malassezia globosa and its pathogenic role in pityriasis versicolor.

Glycosylphosphatidylinositols (GPI)-anchored proteins (GpiPs) are related to the cell wall biogenesis, adhesion, interactions, protease activity, mating, etc. These proteins have been identified in many organisms, including fungi such as Neurospora crassa, Candida albicans, Saccharomyces cerevisiae, and Fusarium graminearum. MGL-3153 gene of Malassezia globosa (M. globosa) encodes a protein which is homologous of the M. restricta, M. sympodialis, M. Pachydermatis, and U. maydis GpiPs. Real-time PCR assay showed that the expression of MGL_3153 gene was significantly up-regulated among M. globosa isolated from patients with pityriasis versicolor (PV) compared to a healthy individual, suggesting the contribution of this gene in the virulence of M. globosa. Accordingly, the sequence of this protein was analyzed by bioinformatics tools to evaluate the structure of that. The conservation analysis of MGL-3153 protein showed that the C-terminal region of this protein, which is responsible for GPI-anchor ligation, was highly conserved during evolution while the N-terminal region just conserved in Malassezia species. Moreover, the predicted tertiary structure of this protein by homology modeling showed that this protein almost has alpha helix structure and represented a stable structure during 150 ns of molecular dynamic simulation. Our results revealed that this protein potentially belongs to GPI-anchored proteins and may contribute to the virulence of M. globosa which warrants further investigations in this area.

Distribution, Prevalence, and Causative Agents of Fungal Keratitis: A Systematic Review and Meta-Analysis (1990 to 2020).

Objectives: This study aims to provide an overview of the prevalence, distribution, and causative agents of fungal keratitis. Methods: All the articles with data on the prevalence of fungal keratitis among various patient groups from January 1, 1990 to May 27, 2020 were retrieved through a systematic search in PubMed, Scopus, Web of Science, and Google Scholar. Data were extracted, and the pooled estimated prevalence of fungal keratitis, yeast/mold infection, the spectrum and frequency of various causative agents, and the pooled estimated prevalence of mixed infections were calculated in general and in various countries (wherever possible) using meta-analysis. Results: From 11,235 articles retrieved in the primary search step, 169 met the inclusion criteria. The 169 eligible articles were divided into six groups and analyzed separately. The pooled prevalence of fungal keratitis was variable with values ranging from 0.05% among postkeratoplasty patients to 43.01% among patients with a clinical suspicion of fungal keratitis. There was also a country-dependent variation in the prevalence (Paraguay: 50.1% (95% CI, 35.11, 65.00); Ireland: 1.1% (95% CI, 0.03, 6.04)). Except for postkeratoplasty cases (yeast: 51.80%), in all patient groups, molds were more common than yeasts. Although more than 50 distinct species of fungi have been found to cause fungal keratitis, Fusarium species followed by Aspergillus species were the most common causes of the disease. In general, 9.29% (95% CI, 6.52, 12.38) of fungal keratitis cases were mixed with bacterial agents. Conclusion: The prevalence of fungal keratitis can vary dramatically depending on the patient groups and geographical origin; however, the dominant causative agents are generally similar.

Identification of new DNA gyrase inhibitors based on bioactive compounds from streptomyces: structure-based virtual screening and molecular dynamics simulations approaches.

DNA gyrase enzyme has vital role in bacterial survival and can be considered as a potential drug target. Owing to the appearance of resistance to gyrase-targeted drugs, especially fluoroquinolone, screening new compounds which bind more efficiently to the mutant binding pocket is essential. Hence, in this work, using Smina Autodock and through structure-based virtual screening of StreptomeDB, several natural products were discovered based on the SimocyclinoneD8 (SD8) binding pocket of GyrA subunit of DNA gyrase. After evaluation of binding affinity, binding modes, critical interactions and physicochemical and pharmaceutical properties, three lead compounds were selected for further analysis. Afterward 60 ns molecular dynamics simulations were performed and binding free energies were calculated by the molecular mechanics/Poisson-Boltzmann surface area method. Also, interaction of the selected lead compounds with the mutated GyrA protein was evaluated. Results indicated that all of the selected compounds could bind to the both wild-type and mutated GyrA with the binding affinities remarkably higher than SimocyclinoneD8. Interestingly, we noticed that the selected compounds comprised angucycline moiety in their structure which could sufficiently interact with GyrA and block the DNA binding pocket of DNA gyrase, in silico. In conclusion, three DNA gyrase inhibitors were identified successfully which were highly capable of impeding DNA gyrase and can be considered as potential drug candidates for treatment of fluoroquinolone-resistant strains.Communicated by Ramaswamy H. Sarma.

Investigation on distribution of airborne fungi in outdoor environment in Tehran, Iran.

BACKGROUND: Airborne fungi are responsible for the majority of fungal infections in humans and animals. Outdoor air markedly influences the prevalence of fungal spore levels in indoor air and thus, it is the major source of fungal infections in indoor environments especially in hospitalized individuals. METHODS: Using a settle plate method, air sampling (1092 air samples from 93 sampling sites in 22 geographic regions of Tehran) was performed by exposing 90 mm settle plates containing Malt extract agar and Potato dextrose agar to the air for 30 min. The plates were incubated at 28°C for 2-3 weeks and examined daily for visible fungal growth. Purified fungal colonies were identified at the genus level based on morphological criteria according to standard methods. RESULTS: A total of 6455 colonies belonging to 24 different fungal genera were isolated. Area V situated in the city center was the most contaminated region with 2523 fungal colonies (39.1%), while area IV in the West showed the least contamination rate (636 colonies; 9.8%). Airborne fungi isolated were classified into 4 classes including hyaline Hyphomycetes (53.5%), dematiaceous Hyphomycetes (41.6%), Zygomycetes (2.8%) and Coelomycetes (0.2%). Aspergillus (31.3%) was the most prominent isolated fungus followed by Cladosporium (22.1%), Penicillium (13.8%) and Alternaria (12.2%). CONCLUSION: Our results indicate that outdoor air is a potential threat to public health because of harboring a wide array of pathogenic and allergenic airborne fungal spores which can serve as the main source of contamination of indoor environments such as homes, offices and hospitals.