Classes Of Antifungals Research Articles

Natural Enfumafungin Analogues from Hormonema carpetanum and Their Antifungal Activities.

Ibrexafungerp, an inhibitor of fungal β-(1,3)-d-glucan synthase, represents the first new class of antifungals to be approved in the last 20 years. Ibrexafungerp is a semisynthetic derivative of the naturally occurring triterpene glycoside enfumafungin. In order to search for new analogues of enfumafungin and to probe its biosynthesis, we undertook a reinvestigation of Hormonema carpetanum, which led to the isolation of two new analogues, enfumafungins B and C, together with enfumafungin. Due to the presence of a hemiacetal moiety in the structure, the enfumafungins appear as a mixture of two interconverting epimers during both the purification process and NMR data acquisition. The structure elucidation, including the differentiation of 25S* and 25R* epimers, was completed by combined analyses of NMR and MS spectroscopic data. The discovery of enfumafungins B and C may have implications for enfumafungin biosynthesis. The antifungal activity of enfumafungins B and C was significantly lower than that of enfumafungin, suggesting that the C-2 substituents and the C-19 carboxy acid are important for activity. Molecular docking simulations revealed significant hydrogen bond interactions between enfumafungins and β-(1,3)-d-glucan synthase, which may be useful for developing new antifungal agents.

Role of the Extracellular Matrix in Candida Biofilm Antifungal Resistance.

Clinical infection due to Candida species frequently involve growth in biofilm communities. Recalcitrance despite antifungal therapy leads to disease persistence associated with high morbidity and mortality. Candida possesses several tools allowing evasion of antifungal effects. Among these, protection of biofilm cells via encasement by the extracellular matrix is responsible for a majority drug resistance phenotype. The Candida matrix composition is complex and includes a mannan-glucan complex linked to antifungal drug sequestration. This mechanism of resistance is conserved across the Candida genus and impacts each of the available antifungal drug classes. The exosome pathway is responsible for delivery and assembly of much of the Candida extracellular matrix as functional vesicle protein and polysaccharide cargo. Investigations demonstrate the vesicle matrix delivery pathway is a useful fungal biofilm drug target. Further elucidation of the vesicle pathway, as well as understanding the roles of biofilm driven cargo may provide additional targets to aid the diagnosis, prevention, and treatment of Candida biofilms.

Enhanced fungal specificity and in vivo therapeutic efficacy of a C-22-modified FK520 analog against C. neoformans.

Fungal infections cause significant morbidity and mortality globally. The therapeutic armamentarium against these infections is limited, and the development of antifungal drugs has been hindered by the evolutionary conservation between fungi and the human host. With rising resistance to the current antifungal arsenal and an increasing at-risk population, there is an urgent need for the development of new antifungal compounds. The FK520 analogs described in this study display potent antifungal activity as a novel class of antifungals centered on modifying an existing orally active FDA-approved therapy. This research advances the development of much-needed newer antifungal treatment options with novel mechanisms of action.

ANTIFUNGAL RESISTANCE: A GROWING CONCERN

Globally, the increasing number of drug-resistant human pathogens represents a major threat to public health. Among these pathogens, fungi that have acquired resistance to the already scarce arsenal of antifungals are of particular significance, as they present therapeutic challenges that increase morbidity and mortality rates. Particularly, most mycoses are opportunistic since they mainly affect hosts with a weakened immune system, including patients with cancer, hematological malignancies, prolonged neutropenia, solid organ transplants, HIV/AIDS, patients in intensive care units, using central venous catheters or on dialysis, using corticosteroids, among others. In most cases, fungal infections have a significant medical and economic burden that outweighs the burden of the underlying disease alone and changes the outcome. In addition, the treatment for mycoses, which consists of four classes of antifungals described several decades ago, polyenes, flucytosine, azoles, and echinocandins, continues to be a major challenge. With the increase in patients at risk, the incidence of mycoses is therefore a growing concern. Considering as well, the scarcity of drugs, together with toxicity, the high price of some formulations, the low availability in low-resource countries, and the development of resistance, there is an urgent need to discover new antifungals or therapeutic strategies or to modify the existing molecules with antifungal activity. This reflection article reveals that various of the most common human fungal pathogens have had the ability to acquire antifungal resistance as antifungal drugs are developed.

Identification of Molecular and Genetic Resistance Mechanisms in a Candida auris Isolate in a Tertiary Care Center in Türkiye.

Candida auris is a multidrug-resistant pathogen that causes nosocomial outbreaks and high mortality. We conducted this study to investigate the molecular mechanisms of antifungal resistance in our clinical isolate of C. auris with a high level of resistance to three main classes of antifungals. A clinical C. auris isolate was identified by MALDI-TOF MS and antifungal susceptibilities were determined by the Sensititre YeastOne YO10 panel. After sequencing the whole genome of the microorganism with Oxford Nanopore NGS Technologies, a phylogenetic tree was drawn as a cladogram to detect where the C. auris clade to this study's assembly belongs. The C. auris isolate in this study (MaCa01) was determined to be a part of the clade I (South Asian). The resistance-related genes indicated that MaCa01 would most likely be highly resistant to fluconazole (CDR1, TAC1b, and ERG11), none or little resistant to amphotericin B (AmpB) and echinocandins, and sensitive to flucytosine. The mutations found in the above-mentioned genes in the Türkiye C. auris isolate reveals an antifungal resistance pattern. This molecular resistance pattern was found consistent with the interpretation of MIC values of the antifungals according to CDC tentative breakpoints. We detected the well-known antifungal resistance mutations, responsible for azole resistance in C. auris. Despite no ERG2, ERG6, and FKS mutation identified, the isolate was found to be resistant to AmpB and caspofungin based on the CDC tentative breakpoints which could be related to unidentified mutations.

Antifungal activity of sustainable histone deacetylase inhibitors against planktonic cells and biofilms of Candida spp. and Cryptococcus neoformans.

The limited therapeutic options for fungal infections and the increased incidence of fungal strains resistant to antifungal drugs, especially Candida spp., require the development of new antifungal drugs and strategies. Histone deacetylase inhibitors (HDACi), like vorinostat, have been studied in cancer treatment and have antifungal effects, acting alone or synergistically with classical antifungals. Here we investigated the antifungal activity of two novel sustainable HDACi (LDT compounds) based on vorinostat structure. In docking simulations, all HDACi analyzed can bind to Class-I HDACs of Candida albicans, Candida tropicalis, and Cryptococcus neoformans, which have similar shapes to vorinostat binding. LDT compounds showed moderate activity when tested alone against fungi but act synergistically with antifungal azoles against Candida spp. They reduced biofilm formation by more than 50% in C. albicans (4µg/mL), with the main action in fungal filamentation. Cytotoxicity of the LDT compounds against RAW264.7 cells was evaluated and LDT536 demonstrated cytotoxicity only at the concentration of 200µmol/L, while LDT537 showed IC50 values of 29.12µmol/L. Our data indicated that these sustainable and inexpensive HDACi have potential antifungal and antibiofilm activities, with better results than vorinostat, although further studies are necessary to better understand the mechanism against fungal cells.

THE INFLUENCE OF MEDICINAL AND AROMATIC PLANTS EXTRACTS ON THE ANTIFUNGAL EFFECT OF FLUCONAZOLE REGARDING C. ALBICANS AND C. TROPICALIS ISOLATED FROM PATIENTS WITH DENTURE STOMATITS

Candida albicans is one of the most common and virulent representatives of Candida fungi which causes fungal lesions of the mucous membranes predominantly in people with compromised immune system. Candida resistance to classical antifungals such as polyenes, azoles, allylamines is a serious practical problem. Imidazole and triazole are the most commonly used antifungal agents for candidiasis today. Their mechanism of action lies in the inhibition of ergosterol biosynthesis which is indispensable for maintaining the structural integrity of fungal cell membranes. Activation of elimination systems is often associated with changes in the structure of fungal membranes, leading to a decrease in the supply of azoles into the fungal cell Screening of antifungal activity and synergism of antifungal activity of 166 aqueous-ethanol plant extracts with Fluconazole in relation to 2 clinical strains of Candida fungi (C.) (C. albicans and C. tropicalis) with different mechanisms of azole resistance isolated from patients with prosthetic stomatitis was conducted by means of agar diffusion method. The expressed direct antifungal activity of extracts of Calendula officinalis L. inflorescences, flowers of Limonium platyphyllum Lincz., flowers of Grataegus monogyna Jacq., roots of Potentilla repens L., the grass of Melilotus albus Medik, leaves of Peucedanum ruthenicum Bieb, leaves of Rhus coriaria L. and aerial part of Polythridum commune Hedw was determined in reference to the tested strains. Synergism of antifungal action with 1/4, 1/8 and 1/32 of Fluconazole MIC (minimal inhibiting concentration) in relation to both test strains of yeast-like Candida fungi was demonstrated by the flowers of Calendula officinalis L, aerial part of Melilotus albus Medik. The main purpose of the screening was to discriminate extracts in order to select those that would be promising for further testing by a more accurate сheckerboard titration method. The efflux mechanism of resistance to triazoles (in C. tropicalis test strain) is more susceptible to modification by biologically active compounds of medicinal plants. Regarding C. albicans test strain which combines the efflux mechanism of resistance with mutation(s) of ergosterol biosynthesis enzymes, the modifying effect of plant extracts is much less frequent and less pronounced. Therefore, it may be assumed that mutations of ergosterol biosynthesis enzymes provide high stability of the phenotypic manifestation of Candida azole resistance. Should that be the case, determining the azole resistance mechanism of Candida clinical isolates may be important for clinical practice. Combination therapy is more beneficial than monotherapy because it may provide more effective destruction or suppression of pathogens. The combined action of synergistic agents is quite easy to achieve in case of localized superficial lesions (which occur on the mucous membranes of the prosthetic bed in candidal prosthetic stomatitis): for example, using a systemic antifungal agent and a topical agent that contains a modifier of resistance of plant origin fungi. Synergistic interactions will increase the therapeutic efficacy of drugs, reduce the likelihood of resistance occurrence or further development, and will reduce dose-related toxicity.

Candida auris Genetics and Emergence.

Candida auris is a multidrug-resistant fungal pathogen that presents a serious threat to global human health. Since the first reported case in 2009 in Japan, C. auris infections have been reported in more than 40 countries, with mortality rates between 30% and 60%. In addition, C. auris has the potential to cause outbreaks in health care settings, especially in nursing homes for elderly patients, owing to its efficient transmission via skin-to-skin contact. Most importantly, C. auris is the first fungal pathogen to show pronounced and sometimes untreatable clinical drug resistance to all known antifungal classes, including azoles, amphotericin B, and echinocandins. In this review, we explore the causes of the rapid spread of C. auris. We also highlight its genome organization and drug resistance mechanisms and propose future research directions that should be undertaken to curb the spread of this multidrug-resistant pathogen.

Lopinavir and ritonavir act synergistically with azoles against Candida auris in vitro and in a mouse model of disseminated candidiasis

The emergence of Candida auris has created a global health challenge. Azole antifungals are the most affected antifungal class because of the extraordinary capability of C. auris to develop resistance against these drugs. Here, we used a combinatorial therapeutic approach to sensitize C. auris to azole antifungals. We have demonstrated the capability of the HIV protease inhibitors lopinavir and ritonavir, at clinically relevant concentrations, to be used with azole antifungals to treat C. auris infections both in vitro and in vivo. Both lopinavir and ritonavir exhibited potent synergistic interactions with the azole antifungals, particularly with itraconazole against 24/24 (100%) and 31/34 (91%) of tested C. auris isolates, respectively. Furthermore, ritonavir significantly interfered with the fungal efflux pump, resulting in a significant increase in Nile red fluorescence by 44%. In a mouse model of C. auris systemic infection, ritonavir boosted the activity of lopinavir to work synergistically with fluconazole and itraconazole and significantly reduced the kidney fungal burden by a 1.2 log (∼94%) and 1.6 log (∼97%) CFU, respectively. Our results urge further comprehensive assessment of azoles and HIV protease inhibitors as a novel drug regimen for the treatment of serious invasive C. auris infections.

#6189 PRECLINICAL VALIDATION OF REPURPOSABLE CANDIDATE DRUG COMPOUNDS FOR CYSTIC NEPHROPATHIES

Abstract Background and Aims Early-onset cystic kidney disease is a clinically and genetically heterogeneous and overlapping group of rare and often severe disorders with limited, mostly symptomatic treatment options. We developed and utilized inherited polycystic cystic kidney disease (PKD) models to search for pharmacological agents that can rescue or mitigate the disease phenotype. Method A high-content screening platform for identification of chemical modifiers of cyst formation and progression in a zebrafish genetic cystic nephropathy model (IFT172 Morpholino-based knockdown in Tg(wt1b:eGFP)), using robotic microscopy with automated image classification and phenotype quantification was used to screen 1280 compounds from the Prestwick library for their cyst-inhibiting activity. Compounds with cyst-inhibitory efficacy and low toxicity in the Zebrafish and oral and trans-placental availability were selected for further study in two rodent PKD models, i.e. PCK and PKD/Mhm (cy/+) rats. Groups of 3-week-old homozygous PCK and heterozygous PKD/Mhm rats were administered orally for 10 weeks three candidate compounds, which included an antihistamine, an anthelmintic and an antifungal agent, or regular ROD16 chow (sick controls). In experimental week 5, blood was taken, and the kidneys were imaged sonographically under anaesthesia. In the last experimental week, glomerular filtration rate was determined by transcutaneous FITC-sinistrin injection. Masson trichrome staining was used to evaluate cyst formation in kidneys. Results 60 compounds with cyst preventive or cyst size reducing activity were identified in the zebrafish screening model. While one third of these compounds caused severe general toxicity, 12 of them showed medium and 4 strong cyst-inhibitory activity with no or mild off-target effects. These substances were from anthelminthic, antihistamine, antifungal and proton pump inhibitor drug classes. Preliminary results in the rodent models suggest that anthelminthic treatment reduced the number of cysts in female (3.3±1.3 vs. untreated control, 5.4±0.9) but not male PCK rats (3.7±0.6 vs. 3.9±0.7) after 10 weeks of treatment. These changes were accompanied by improved glomerular filtration rate (GFR) in treated females (t½: 0.22±0.04 min vs. 0.3±0 min). An improvement in GFR was also observed in female PKD/Mhm rats after 10 weeks of treatment with the anthelmintic compound compared to untreated control animals (t½: 0.24±0.06 vs. 0.51±0.16 min, p = 0.02). Conclusion Candidate cyst-inhibitory drugs identified in a zebrafish model were applied in rat models of PKD. The administration of an anthelmintic agent had a positive impact on the progression of polycystic kidney disease. The beneficial effect appears to be sex specific. If further corroborated, our findings may allow repurposing of a drug approved for another indication to slow disease progression in patients with cystic kidney diseases.

Antifungal drugs

Fungal infections continue to emerge as an important cause of infectious disease and mortality in humans. Amphotericin B deoxycholate (ABD), was the first antifungal that was discovered, and it was released in 1958, and flucytosine, which was developed later and is effective against Candida and Cryptococcus, was introduced in 1978. The discovery of first-generation azoles (fluconazole and itraconazole) in the 1990s has created a new step in the treatment of fungi. In the years that followed, with the development of lipid formulations of amphotericin B, the introduction of second-generation azoles, and the release of the most recently developed class, echinocandins, the foundations of today’s existing antifungal classes were laid. This article is aimed to review the mechanism of action, side effects and clinical use indications of the main antifungal drugs used in the treatment of systemic fungal infections.

Candidemia - Species Distribution and Antifungal Resistance Patterns in Two Tertiary Care Centers in South India

Background: Bloodstream infections due to Candida species are a significant cause of morbidity and mortality in hospitalized patients worldwide. Epidemiology of Candidemia is dynamic with reports of non-albicans Candida species on a steady increase and the emergence of C.auris reported from many centers in India. This study was undertaken to analyze species distribution and antifungal susceptibility of Candida bloodstream infections in two tertiary care centers in Telangana, South India. Material and Methods: In a retrospective analysis, Candida isolates from blood cultures of patients with suspected bloodstream infection over five years (2017-2021) were identified and tested for antifungal susceptibility by Vitek 2 Compact (Biomerieux, France). Results: A total of 85,603 blood cultures were processed from two centers from January 2017 to December 2021. Among these, 270 (0.31%) Candida species were isolated. Of the total Candida isolates, C. tropicalis (49.2%) was the most common isolate, followed by C. albicans 55 (20.3%), C. glabrata 35 (12.9%), C. parapsilosis 25 (9.2%), C. auris (5.5%), C. guilliermondii (1.4%) and C. krusei (1.1%). We have tested six antifungals and of the total isolates, resistance to fluconazole was highest (11.9%) followed by amphotericin B (7.0%), caspofungin (2.9%), voriconazole (2.3%), flucytosine (1.8%) and micafungin (0.7%). C.auris isolates were found to be resistant to two or three classes of antifungals tested and 13.3% were pandrug -resistant. Conclusion: C.tropicalis was the most common isolate and each Candida species showed varied antifungal resistance rates. We emphasize the need for the identification of Candida species and antifungal susceptibility for every invasive isolate to tailor targeted preventive and therapeutic antifungal strategies in line with current evidence and guidelines.

Efficacy and safety of echinocandin monotherapy and combination therapy for immunocompromised patients with systemic candidiasis: A systematic review and meta-analysis.

Systemic candidiasis is caused by Candida invading the bloodstream. The efficacy and safety of echinocandins in monotherapy and combination therapy regimes have not been adequately compared in immunocompromised patients with Candidiasis, and thus this systematic review aims to do so. A protocol was prepared a priori. PubMed, Embase and Cochrane Library databases were searched systematically (from inception of each database to September 2022) to identify randomized controlled trials. Two reviewers performed screening, quality assessment of trials, and extracted data independently. Pairwise meta-analysis was performed using random-effects model to compare echinocandin monotherapy versus other antifungals. The primary outcomes of interest were treatment success and treatment-related adverse events. 547 records (PubMed=310, EMBASE=210 and Cochrane Library=27) were reviewed. Following our screening criteria, six trials involving 177 patients were included. Risk of bias of four included studies had some concerns due to lack of a pre-specified analysis plan. Meta-analysis shows that echinocandin monotherapy does not have significantly higher rates of "treatment success" compared to other classes of antifungals (RR 1.12, 95%CI 0.80-1.56). However, echinocandins appeared to be significantly safer than other forms of antifungal therapy (RR 0.79, 95%CI 0.73-0.86). Our findings have shown that echinocandin monotherapy (micafungin, caspofungin) given intravenously are just as effective as other antifungals (amphotericin B, itraconazole) in the treatment of systemic candidiasis in immunocompromised patients. There appears to be similar benefits when using echinocandins compared to amphotericin B which has also been used as a broad-spectrum antifungal, while avoiding the severe adverse effects that amphotericin B causes, such as nephrotoxicity.

Uji aktivitas antimikroba ekstrak etanol buah renggak (Amomum dealbatum Roxb.) terhadap Staphylococcus aureus dan Candida albicans

Staphylococcus aureus and Candida albicans are microorganisms that cause infection in humans and have developed resistance to several classes of antibiotics and antifungals. Plants in the genus Amomum have been used in traditional medicine and have scientific potential as alternatives to natural antibacterial and antifungal agents. Renggak (Amomum dealbatum Roxb.) is a species of the genus Amomum that is commonly found in Lombok. Scientific research related to the antibacterial and antifungal activity of the fruit is still limited. The aim of this study was to determine the antibacterial and antifungal activity of ethanol extract of renggak fruit against Staphylococcus aureus and Candida albicans. The extraction method used sonication with 96% ethanol. Testing of antibacterial and antifungal activity by disc diffusion method. The positive control used chloramphenicol for antibacterial testing and ketoconazole for antifungal testing, while the negative control used 10% DMSO solution. The antibacterial and antifungal activity of the extract was measured based on the diameter of the inhibition zone formed around the disc. Data analysis used the Kruskall-Wallis statistical test with a 95% confidence level. The results showed that the ethanol extract had moderate activity against S. aureus at concentrations of 20% w/v & 30%w/v with inhibitory diameters ranging from 5-7 mm, while at concentrations of 40% w/v & 50% w/v. has strong activity with inhibitory diameters ranging from 10-15 mm. The ethanol extract showed no activity at concentrations of 50%, 75%, and 100% in inhibiting the growth of the fungus C. albicans. Statistical test of each extract concentration had a significant effect on the inhibition of growth of S. aureus compared to the negative control. Based on the description above, it can be concluded that the extract of renggak fruit has the potential to inhibit the growth of S. aureus.

A One Health approach to overcoming fungal disease and antifungal resistance.

The global burden of fungal disease poses a substantial threat to human, animal, and environmental health, endangering both human and livestock populations and creating vulnerabilities to food supplies world-wide. Antifungal drugs provide essential therapies to humans and animals against infections, while fungicides provide protection in agriculture. However, a limited arsenal of antifungal agents results in cross-use between agriculture and health, promoting the development of resistance, and drastically reducing our defenses against disease. Critically, antifungal resistant strains found ubiquitously within the natural environment demonstrate resistance to the same classes of antifungals used to treat human and animal infections, hindering effective treatment within the clinic. This interconnectivity supports the need for a One Health approach to combat fungal diseases and overcome antifungal resistance, ensuring that treatment and protection of a defined group does not inadvertently endanger or sacrifice other plants, animals, or humans. In this review, we present sources of antifungal resistance and discuss the integration of environmental and clinical resources to manage disease. Moreover, we explore opportunities for drug synergy and repurposing strategies, highlight fungal targets being investigated to overcome resistance, and propose technologies for the discovery of novel fungal targets. This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology.

Candida auris as a pathogen that can cause emerging infectious disease: a literature review

Candida auris is a fungal pathogen that can cause emerging infectious disease and infections related to health services (healthcare-associated infections) and threaten global health. It is one of the causes of candidemia, which has been connected to outbreaks and high mortality rates in medical facilities all over the world. Hospitalized patients who are critically ill, primarily in intensive care unit settings, account for the majority of reported infections. C. auris can be multi-resistant to various antifungal classes commonly used to treat other Candida infections. Invasive infection due to C. auris causes high mortality and morbidity rates. C. auris easily survives long enough in the surrounding environment to cause the rapid spread of outbreaks in health facilities. The critical need for novel, candidate antifungal medicines for C. auris therapies is driven by the pathogenicity, drug resistance, and widespread distribution of C. auris. In limiting the spread of C. auris, prompt investigations and aggressive interventions are required. These include alerting public health agencies, implementing contact precautions, thoroughly cleaning and disinfecting the environment, performing infection control assessments, tracing and screening contacts for colonization, reviewing the history of microbiology tests, and conducting prospective surveillance for cases at labs. C. auris poses a unique challenge in clinical settings due to its identification challenges, multidrug resistance traits, evolution of virulence factors, associated high patient fatality rates, and long-term survival on surfaces in the environment. This study aims to understand the epidemiology, clinical manifestations, characteristics, virulence factors, methods of identification, therapy and prevention control of infection by C. auris.

Amesia hispanica sp. nov., Producer of the Antifungal Class of Antibiotics Dactylfungins.

During a study of the diversity of soilborne fungi from Spain, a strain belonging to the family Chaetomiaceae (Sordariales) was isolated. The multigene phylogenetic inference using five DNA loci showed that this strain represents an undescribed species of the genus Amesia, herein introduced as A. hispanica sp. nov. Investigation of its secondary metabolome led to the isolation of two new derivatives (2 and 3) of the known antifungal antibiotic dactylfungin A (1), together with the known compound cochliodinol (4). The planar structures of 1-4 were determined by ultrahigh performance liquid chromatography coupled with diode array detection and ion mobility tandem mass spectrometry (UHPLC-DAD-IM-MS/MS) and extensive 1D and 2D nuclear magnetic resonance (NMR) spectroscopy after isolation by HPLC. All isolated secondary metabolites were tested for their antimicrobial and cytotoxic activities. Dactylfungin A (1) showed selective and strong antifungal activity against some of the tested human pathogens (Aspergillus fumigatus and Cryptococcus neoformans). The additional hydroxyl group in 2 resulted in the loss of activity against C. neoformans but still retained the inhibition of As. fumigatus in a lower concentration than that of the respective control, without showing any cytotoxic effects. In contrast, 25″-dehydroxy-dactylfungin A (3) exhibited improved activity against yeasts (Schizosaccharomyces pombe and Rhodotorula glutinis) than 1 and 2, but resulted in the appearance of slight cytotoxicity. The present study exemplifies how even in a well-studied taxonomic group such as the Chaetomiaceae, the investigation of novel taxa still brings chemistry novelty, as demonstrated in this first report of this antibiotic class for chaetomiaceous and sordarialean taxa.

Salvage Treatment for Invasive Aspergillosis and Mucormycosis: Challenges, Recommendations and Future Considerations.

Invasive mold diseases are devastating systemic infections which demand meticulous care in selection, dosing, and therapy monitoring of antifungal drugs. Various circumstances regarding PK/PD properties of the applied drug, resistance/tolerance of the causative pathogen or host intolerability can lead to failure of the initial antifungal therapy. This necessitates treatment adaption in the sense of switching antifungal drug class or potentially adding another drug for a combination therapy approach. In the current state of drastically limited options of antifungal drug classes adaption of therapy remains challenging. Current guidelines provide restricted recommendations only and emphasize individual approaches. However, novel antifungals, incorporating innovative mechanisms of action, show promising results in late stage clinical development. These will expand options for salvage therapy in the future potentially as monotherapy or in combination with conventional or other novel antifungals. We outline current recommendations for salvage therapy including PK/PD considerations as well as elucidate possible future treatment options for invasive aspergillosis and mucormycosis.

Evaluation of Protein Kinase C Inhibition of some Benzofuro[3,2-d]pyrimidine Derivatives

Abstract: Treatment of fungal infections is very difficult because of the limited therapeutic arsenal and the emergence of resistance to the two major antifungal classes: azoles and echinocandins. Consequently, finding new targets and new therapeutic strategies is a priority. The protein kinase Pkc1 of Candida albicans (CaPkc1), one of the key proteins involved in MAPK pathways, is described as a regulator of cell wall integrity during growth, morphogenesis, and response to cell wall stress. Therefore, the discovery of CaPkc1 inhibitory molecules can open up new and promising prospects in the development of new antifungal drugs that inhibit CaPkc1. In this study, we evaluated the CaPkc1 inhibitory activity of three benzofuro[3,2-d]pyrimidine derivatives at three different concentrations of 50 µM, 100 µM, and 150 µM. A concentration of 100 μM was optimal for CaPkc1 inhibitory activity with all three benzofuro[3,2-d]pyrimidine derivatives.
 Keywords: Benzofuro[3,2-d]pyrimidine, CaPkc1, Candida albicans, antifungal activity. 
 

Potential Strategies to Control the Risk of Antifungal Resistance in Humans: A Comprehensive Review

Fungal infections are becoming one of the main causes of morbidity and mortality in people with weakened immune systems. Mycoses are becoming more common, despite greater knowledge and better treatment methods, due to the regular emergence of resistance to the antifungal medications used in clinical settings. Antifungal therapy is the mainstay of patient management for acute and chronic mycoses. However, the limited availability of antifungal drug classes limits the range of available treatments. Additionally, several drawbacks to treating mycoses include unfavourable side effects, a limited activity spectrum, a paucity of targets, and fungal resistance, all of which continue to be significant issues in developing antifungal drugs. The emergence of antifungal drug resistance has eliminated accessible drug classes as treatment choices, which significantly compromises the clinical management of fungal illnesses. In some situations, the emergence of strains resistant to many antifungal medications is a major concern. Although new medications have been developed to address this issue, antifungal drug resistance has grown more pronounced, particularly in patients who need long-term care or are undergoing antifungal prophylaxis. Moreover, the mechanisms that cause resistance must be well understood, including modifications in drug target affinities and abundances, along with biofilms and efflux pumps that diminish intracellular drug levels, to find novel antifungal drugs and drug targets. In this review, different classes of antifungal agents, and their resistance mechanisms, have been discussed. The latter part of the review focuses on the strategies by which we can overcome this serious issue of antifungal resistance in humans.