Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from Aspergillus fumigatus: In Silico Drug Design Studies

Chitinases represent an alternative therapeutic target for opportunistic invasive mycosis since they are necessary for fungal cell wall remodeling. This study presents the design of new chitinase inhibitors from a known hydrolysis intermediate. Firstly, a bioinformatic analysis of Aspergillus fumigatus chitinase B1 (AfChiB1) and chitotriosidase (CHIT1) by length and conservation was done to obtain consensus sequences, and molecular homology models of fungi and human chitinases were built to determine their structural differences. We explored the octahydroisoindolone scaffold as a potential new antifungal series by means of its structural and electronic features. Therefore, we evaluated several synthesis-safe octahydroisoindolone derivatives by molecular docking and evaluated their AfChiB1 interaction profile. Additionally, compounds with the best interaction profile (1–5) were docked within the CHIT1 catalytic site to evaluate their selectivity over AfChiB1. Furthermore, we considered the interaction energy (MolDock score) and a lipophilic parameter (aLogP) for the selection of the best candidates. Based on these descriptors, we constructed a mathematical model for the IC50 prediction of our candidates (60–200 μM), using experimental known inhibitors of AfChiB1. As a final step, ADME characteristics were obtained for all the candidates, showing that 5 is our best designed hit, which possesses the best pharmacodynamic and pharmacokinetic character.

MUCORMYCOSI (BLACK FUNGUS): A REVIEW

Mucormycosis is a new angioinvasive infection caused by the ubiquitous filamentous fungus of the Mucorales order of the Zygomycete class. Mucormycosis has emerged as the third most prevalent invasive mycosis in patients undergoing hematological and allogeneic stem cell transplantation, following candidiasis and aspergillosis. Sporangiospores must be inhaled on a daily basis. Members of the Mucorales are very infrequent in nasal mucus, indicating that spores in airway mucus are removed via mucociliary transport or that there is a minimal degree of airborne contamination.

The importance of developing new mannan tests in the diagnosis of invasive candidiasis in oncology patients

The regimens of anticancer therapy have been intensified and methods of high-dose chemotherapy (HDCT) have been introduced for recent years which made it possible to achieve significant progress in the results of tumor treatments. Intensification of chemotherapy regimens in cancer patients leads to the emergence of risk factors of invasive candidiasis (IC) development: agranulocytosis, disruption of the integrity of the mucous membranes, prolonged use of CVC, repeated antibiotic therapy, long-term parenteral nutrition. Thus, intensification of anticancer therapy may be accompanied by an increase in infection-mediated mortality.IC is the most common invasive mycosis in Russia. More than 11 thousand cases of IC occur in our country every year. The frequency IC in Russia is 8.29 per 100 thousand of the population, which corresponds to the results of the LIFE study in European countries where this indicator varies from 2.2 to 11 per 100 thousand of the population. There are no clinical signs or symptoms specific for IC. It develops in patients with concomitant diseases, which significantly complicates the diagnosis. In this regard, an urgent issue is to improve the diagnosis of candidal infectious complications in cancer patients in order to optimize treatment by studying serological markers that have the greatest value in the diagnosis of infectious complications in cancer patients.

Invasive fungal infection of the central nervous system caused by rare yeast pathogen Malassezia spp. in patients with acute leukemia: case reports and literature review

Malassezia spp. is a commensal yeast that represents normal microflora in humans and some animals. However, Malassezia spp. can cause life-threatening invasive mycosis. Evidence on Malassezia spp. infections is limited mostly to a case reports describing disease in newborns and premature infants, because lipid infusions (total parenteral nutrition) given through central venous catheter is a major risk factor. Here, we report two cases of CNS infection caused by Malassezia species in non-neonates with acute leukemia.

Cryptococcal Virulence in Humans: Learning From Translational Studies With Clinical Isolates

Cryptococcosis, an invasive mycosis caused by Cryptococcus spp, kills between 20% and 70% of the patients who develop it. There are no vaccines for prevention, and treatment is based on a limited number of antifungals. Studying fungal virulence and how the host responds to infection could lead to new therapies, improving outcomes for patients. The biggest challenge, however, is that experimental cryptococcosis models do not completely recapitulate human disease, while human experiments are limited due to ethical reasons. To overcome this challenge, one of the approaches used by researchers and clinicians is to: 1) collect cryptococcal clinical isolates and associated patient data; 2) study the set of isolates in the laboratory (virulence and host-pathogen interaction variables, molecular markers); 3) correlate the laboratory and patient data to understand the roles fungal attributes play in the human disease. Here we review studies that have shed light on the cryptococcosis pathophysiology using these approaches, with a special focus on human disease. Isolates that more effectively evade macrophage responses, that secrete more laccase, melanize faster and have larger capsules in the cerebrospinal fluid are associated with poorer patient outcomes. Additionally, molecular studies have also shown that cryptococcal clades vary in virulence, with clinical impact. Limitations of those studies include the use of a small number of isolates or retrospectively collected clinical data. The fact that they resulted in very important information is a reflection of the impact this strategy has in understanding cryptococcosis and calls for international collaboration that could boost our knowledge.

The Emericellipsins A–E from an Alkalophilic Fungus Emericellopsis alkalina Show Potent Activity against Multidrug-Resistant Pathogenic Fungi

Novel antimicrobial peptides with antifungal and cytotoxic activity were derived from the alkalophilic fungus Emericellopsis alkalina VKPM F1428. We previously reported that this strain produced emericellipsin A (EmiA), which has strong antifungal and cytotoxic properties. Further analyses of the metabolites obtained under a special alkaline medium resulted in the isolation of four new homologous (Emi B–E). In this work, we report the complete primary structure and detailed biological activity for the newly synthesized nonribosomal antimicrobial peptides called emericellipsins B–E. The inhibitory activity of themajor compound, EmiA, against drug-resistant pathogenic fungi was similar to that of amphotericin B (AmpB). At the same time, EmiA had no hemolytic activity towards human erythrocytes. In addition, EmiA demonstrated low cytotoxic activity towards the normal HPF line, but possessed cancer selectivity to the K-562 and HCT-116 cell lines. Emericillipsins from the alkalophilic fungus Emericellopsis alkaline are promising treatment alternatives to licensed antifungal drugs for invasive mycosis therapy, especially for multidrug-resistant aspergillosis and cryptococcosis.

Isolation of Cryptococcus spp. from several environmental niches in São Luís, MA

Cryptococcosis is an invasive mycosis triggered by a complex of fungal pathogens present in various environmental niches. Cryptococcus neoformans, C. gattii, and emerging pathogens such as C. laurentii and C. albidus are found in aged excreta of Columba livia (pigeon), its natural disseminator. As the pigeon population has increased in São Luís, the objective of this research was to demonstrate the presence of Cryptococcus spp. in the excreta of C. livia in public environments. Twenty-three samples were collected at 14 sites, dispensed into conical tubes, homogenized with saline and chloramphenicol, and allowed to rest until processing. Twenty-four hours after collection, aliquots were distributed in a fungal culture medium and incubated. The macromorphological examination revealed levaduriform, mucoid, bright, isolated colonies compatible with Cryptococcus spp. In the micromorphological examination, 11 of the 23 samples (42.85%) showed the presence of cells with a thick, refringent capsule and mucopolysaccharide around the blastoconidia, typical of Cryptococcus spp. fungi. The other samples (57.14%) were negative for the fungus. The environmental isolation of this fungus in public areas is relevant to public health since the growing pigeon population in São Luís increases the risk of exposure and infection by dispersion of infectious propagules in the environment.

Echinocandins: structural diversity, biosynthesis, and development of antimycotics

Echinocandins are a clinically important class of non-ribosomal antifungal lipopeptides produced by filamentous fungi. Due to their complex structure, which is characterized by numerous hydroxylated non-proteinogenic amino acids, echinocandin antifungal agents are manufactured semisynthetically. The development of optimized echinocandin structures is therefore closely connected to their biosynthesis. Enormous efforts in industrial research and development including fermentation, classical mutagenesis, isotope labeling, and chemical synthesis eventually led to the development of the active ingredients caspofungin, micafungin, and anidulafungin, which are now used as first-line treatments against invasive mycosis. In the last years, echinocandin biosynthetic gene clusters have been identified, which allowed for the elucidation but also engineering of echinocandin biosynthesis on the molecular level. After a short description of the history of echinocandin research, this review provides an overview of the current knowledge of echinocandin biosynthesis with a special focus of the diverse structural elements, their biosynthetic background, and structure−activity relationships. Key points • Complex and highly oxidized lipopeptides produced by fungi. • Crucial in the design of drugs: side chain, solubility, and hydrolytic stability. • Genetic methods for engineering biosynthesis have recently become available.

Occult Talaromyces marneffei Infection Unveiled by the Novel Mp1p Antigen Detection Assay

Talaromyces marneffei causes fatal invasive mycosis in Southeast Asia. Diagnosis by culture has limited sensitivity and can result in treatment delay. We describe the use of a novel Mp1p enzyme immunoassay (EIA) to identify blood culture–negative talaromycosis, subsequently confirmed by bone marrow cultures. This EIA has the potential to speed diagnosis, enabling early therapy initiation.