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The trend of increasing incidence of skin diseases of various etiologies and the frequency of complications caused by them (dermatitis, allergies, secondary infections, eczema, trichophytosis, dermatophytosis, dermatomycosis, etc.) is increasing in Ukraine. Nowadays the important problem is the development of new domestic effective medicines to combat this pathology. The general market of veterinary drugs, feed additives of finished feed, and premixes was investigated, and the place of drugs used to combat fungal diseases of animal skin was determined to identify the current state and prospects for the development of domestic veterinary drugs (DVD) production. It is established that the studied range of the market saturation structure of veterinary drugs, feed additives, finished feeds, and premixes have significant competition in the pharmaceutical market of Ukraine from foreign manufacturers. The range of effective domestic medicines for the treatment of fungal skin diseases of animals based on domestic substances is very minor, so there are prospects for the introduction into production and further promotion of new effective drugs in this area on the domestic market. The aim of the work is to determine the current state and prospects for the development of the production of national veterinary medicines for the treatment of fungal diseases of animal skin based on the study of the structure of the general market for veterinary drugs, feed additives, finished feed, premixes and determination of their market share. Materials and methods. The following methods (synthetic, analytical, information search, descriptive, generalization) were used in the work. The research materials were literary sources that contain information on the structure of the veterinary market of antifungal and antimicrobial drugs and the “List of Registration of Veterinary Drugs, Feed Additives, and Finished Feeds” as of July 21, 2022. Results. According to the above List, it was found that as of 21.07.2022, 6574 trade names of these products were registered on the Ukrainian market of veterinary medicines, feed additives, finished feed, and premixes. 5097 (77.53 %) of which were supplied by foreign manufacturers, the rest – 1497 (22.47 %) were products of domestic manufacturers. The geography of suppliers is represented by 47 countries, including Ukraine. France, Poland, and Germany remain the leaders in terms of the number of registered items of drugs, feed additives, finished feeds, and premixes. Based on the marketing analysis, it was found that in terms of dosage forms, this market is overly heterogeneous and is represented by 31 dosage forms, which are powders, liquid, solid, soft, and gaseous forms by consistency. It has been proved that a small assortment of antifungal DVDs makes it possible to saturate this segment of the pharmaceutical market not only with imported drugs, but also to find opportunities for the creation and introduction of fundamentally new antifungal DVDs to the domestic market. Conclusions. The development and introduction of new antifungal drugs to the market for further use in the treatment of skin diseases are important. It will contribute to improving the effectiveness of prevention and treatment of the above diseases and will allow the offering of effective innovative pharmacotherapeutic drugs to domestic veterinary practice.

Currently, the spread of fungal infections is becoming an urgent problem. Fungi of the Candida genus are opportunistic microorganisms that cause superficial and life-threatening systemic candidiasis in immunocompromised patients. The list of antifungal drugs for the treatment of candidiasis is very limited, while the prevalence of resistant strains is growing rapidly. Therefore, the search for new antimycotics, including those exhibiting immunomodulatory properties, is of great importance. Plenty of natural compounds with antifungal activities may be extremely useful in solving this problem. This review evaluates the features of natural antimicrobial peptides, namely plant defensins as possible prototypes of new anticandidal agents. Plant defensins are important components of the innate immune system, which provides the first line of defense against pathogens. The introduction presents a brief summary regarding pathogenic Candida species, the pathogenesis of candidiasis, and the mechanisms of antimycotic resistance. Then, the structural features of plant defensins, their anticandidal activities, their mechanisms of action on yeast-like fungi, their ability to prevent adhesion and biofilm formation, and their combined action with conventional antimycotics are described. The possible mechanisms of fungal resistance to plant defensins, their cytotoxic activity, and their effectiveness in in vivo experiments are also discussed. In addition, for the first time for plant defensins, knowledge about their immunomodulatory effects is also presented.

Naturally occurring echinocandin B and FR901379 are potent antifungal lipopeptides featuring a cyclic hexapeptide nucleus and a fatty acid side chain. They are the parent compounds of echinocandin drugs for the treatment of severe fungal infections caused by the Candida and Aspergilla species. To minimize hemolytic toxicity, the native fatty acid side chains in these drug molecules are replaced with designer acyl side chains. The deacylation of the N-acyl side chain is, therefore, a crucial step for the development and manufacturing of echinocandin-type antibiotics. Echinocandin E (ECE) is a novel echinocandin congener with enhanced stability generated via the engineering of the biosynthetic machinery of echinocandin B (ECB). In the present study, we report the discovery of the first echinocandin E acylase (ECEA) using the enzyme similarity tool (EST) for enzymatic function mining across protein families. ECEA is derived from Streptomyces sp. SY1965 isolated from a sediment collected from the Mariana Trench. It was cloned and heterologously expressed in S. lividans TK24. The resultant TKecea66 strain showed efficient cleavage activity of the acyl side chain of ECE, showing promising applications in the development of novel echinocandin-type therapeutics. Our results also provide a showcase for harnessing the essentially untapped biodiversity from the hadal ecosystems for the discovery of functional molecules.

Background: Combination antifungal therapy has become a prominent approach in medical practice as it takes advantage of synergistic interactions by interfering with multiple targets of the pathogen, broadening the spectrum of activity, reducing the development of resistance, and improving treatment outcomes. Therefore, combining conventional antifungal drugs with natural products can increase antifungal activity, reduce side effects, and optimize therapeutic effects. Purpose: The present study aimed to evaluate the antifungal activity of thyme essential oil (ThyEO) in combination with amphotericin B, caspofungin, fluconazole, itraconazole, and posaconazole (PSZ), as well as its inhibitory effect on Candida albicans virulence factors. Materials and Methods: The microbroth dilution assay was employed to determine the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC). Interactions were assessed using the microdilution checkerboard assay. Ergosterol and methylene blue assays were used to detect effects on fungal membrane, while the sorbitol assay was used to detect effects on fungal cell wall. Inhibition of yeast virulence factors (adherence to epithelial cells, germ tube and pseudomycelium formation, secretion of hydrolytic enzymes, and biofilm formation) was assessed with previously reported methods. Results: Almost all combinations showed additivism against C. albicans, except ThyEO/PSZ (31.25/0.0039 µg/ml), which showed partial synergism. Furthermore, all mixtures were fungicidal against C. albicans strains. ThyEO/PSZ, its components alone, and thymol were shown to disrupt the fungal cytoplasmic membrane, increasing its permeability. ThyEO/PSZ, at sub-inhibitory concentrations, significantly decreased the ability of C. albicans to adhere to buccal epithelial cells. ThyEO/PSZ, ThyEO, and PSZ were able to reduce the pseudomycelium production of C. albicans while thymol completely inhibited its formation. ThyEO/PSZ, each combination component on its own, and thymol inhibited biofilm formation and preformed biofilm of C. albicans. Notably, ThyEO/PSZ showed synergistic and fungicidal activity against a resistant strain of C. albicans, reducing the PSZ dose by 4-fold. Conclusion: These findings make ThyEO and ThyEO/PSZ mixture valuable candidates for the development of alternative antifungals with a lower incidence of adverse effects.

Reactive oxidant species (ROS) are unstable, highly reactive molecules that are produced by cells either as byproducts of metabolism or synthesized by specialized enzymes. ROS can be detrimental, e.g., by damaging cellular macromolecules, or beneficial, e.g., by participating in signaling. An increasing body of evidence shows that various fungal species, including both yeasts and molds, increase ROS production upon exposure to the antifungal drugs currently used in the clinic: azoles, polyenes, and echinocandins. However, the implications of these findings are still largely unclear due to gaps in knowledge regarding the chemical nature, molecular origins, and functional consequences of these ROS. Because the detection of ROS in fungal cells has largely relied on fluorescent probes that lack specificity, the chemical nature of the ROS is not known, and it may vary depending on the specific fungus-drug combination. In several instances, the origin of antifungal drug-induced ROS has been identified as the mitochondria, but further experiments are necessary to strengthen this conclusion and to investigate other potential cellular ROS sources, such as the ER, peroxisomes, and ROS-producing enzymes. With respect to the function of the ROS, several studies have shown that they contribute to the drugs’ fungicidal activities and may be part of drug-induced programmed cell death (PCD). However, whether these “pro-death” ROS are a primary consequence of the antifungal mechanism of action or a secondary consequence of drug-induced PCD remains unclear. Finally, several recent studies have raised the possibility that ROS induction can serve an adaptive role, promoting antifungal drug tolerance and the evolution of drug resistance. Filling these gaps in knowledge will reveal a new aspect of fungal biology and may identify new ways to potentiate antifungal drug activity or prevent the evolution of antifungal drug resistance.

Azole compounds, commonly used antifungal agents for the treatment of systemic fungal infections, have been confirmed to show inhibition to some P450 enzymes. However, the potential inhibition or interaction mechanism is elusive. Here, the detailed interaction between first‐generation antifungal agents (miconazole, and its derivatives fluconazole and voriconazole) and CYP2C9 are studied using docking and molecular dynamics (MD) simulation methods. Docking results show that azoles are mainly located in the cavity formed by helices A, F, I, and heme group. MD results indicate flu‐1 and vor‐2 undergo large conformational changes mediated by inter/intramolecular hydrogen bonds (H‐bonds), while other azole conformations exhibit low flexibility in the active site. Interestingly, one water (W7255) joins the interaction between flu‐1 and N204, implying the significance of water in regulating the binding of fluconazole. MM‐GBSA analysis manifests that miconazole possesses highest binding affinity compared to fluconazole and voriconazole, which agrees well with previous reports. Moreover, the per‐residue decomposition suggests that the favorable interactions are dominated by ΔGvdW and ΔGnonpl between azoles and residues (V113/F114, I205/L208, A297/E300/T301, F476/A477) and ΔGvdW should be further ascribed to CH⋯Cl, CH⋯N, CH⋯O and CH⋯π interactions. [ABSTRACT FROM AUTHOR]

[Display omitted] Repurposing antifungal drugs in cancer therapy has attracted unprecedented attention in both preclinical and clinical research due to specific advantages, such as safety, high-cost effectiveness and time savings compared with cancer drug discovery. The surprising and encouraging efficacy of antifungal drugs in cancer therapy, mechanistically, is attributed to the overlapping targets or molecular pathways between fungal and cancer pathogenesis. Advancements in omics, informatics and analytical technology have led to the discovery of increasing "off-site" targets from antifungal drugs involved in cancerogenesis, such as smoothened (D477G) inhibition from itraconazole in basal cell carcinoma. This review illustrates several antifungal drugs repurposed for cancer therapy and reveals the underlying mechanism based on their original target and "off-site" target. Furthermore, the challenges and perspectives for the future development and clinical applications of antifungal drugs for cancer therapy are also discussed, providing a refresh understanding of drug repurposing. This review may provide a basic understanding of repurposed antifungal drugs for clinical cancer management, thereby helping antifungal drugs broaden new indications and promote clinical translation. [ABSTRACT FROM AUTHOR]

Invasive fungal infections are associated with significant morbidity and mortality, and their management is restricted to a variety of agents from five established classes of antifungal medication. In practice, existing antifungal agents are often constrained by dose-limiting toxicities, drug interactions, and the routes of administration. An increasing prevalence of invasive fungal infections along with rising rates of resistance and the practical limitations of existing agents has created a demand for the development of new antifungals, particularly those with novel mechanisms of action. This article reviews antifungal agents currently in various stages of clinical development. New additions to existing antifungal classes will be discussed, including SUBA-itraconazole, a highly bioavailable azole, and amphotericin B cochleate, an oral amphotericin formulation, as well as rezafungin, a long-acting echinocandin capable of once-weekly administration. Additionally, novel first-in-class agents such as ibrexafungerp, an oral glucan synthase inhibitor with activity against various resistant fungal isolates, and olorofim, a pyrimidine synthesis inhibitor with a broad spectrum of activity and oral formulation, will be reviewed. Various other innovative antifungal agents and classes, including MGCD290, tetrazoles, and fosmanogepix, will also be examined.

Oral mucositis is highly prevalent among the elderly, for whom oral care is often difficult. Oral mucositis, such as candidiasis, can induce systemic fungemia. Antifungal prophylaxis may be useful in such cases to prevent systemic fungemia; however, studies on this are limited. The objective of this study was to demonstrate the effectiveness of antifungal prophylaxis to prevent systemic Candida dissemination compared to oral care using a mice model. Oral candidiasis was induced using chemotherapy and inoculation with C. albicans in 8-week-old male mice. Group A was given oral care, Group B was orally administered an antifungal drug, Group C was intravenously administered an antifungal drug, and Group D was used as the negative control group. Macroscopic features of the tongue surface, colony forming units (CFU) on the tongue, and blood culture for C. albicans were evaluated. CFU was significantly higher in Group A than in Groups B and C. The oral care group, but not the groups administered antifungal agents, showed significantly higher positive numbers of animals with C. albicans in the blood as compared to the control group, indicating the effectiveness of antifungal prophylaxis over oral care. Antifungal prophylaxis may be an option for the prevention of systemic fungemia in individuals with difficulty in oral care.

Antifungal drugs prevent topical or invasive fungal infections (mycoses) either by stopping growth of fungi (termed fungistatic) or by killing the fungal cells (termed fungicidal). Antibiotics also prevent bacterial infections through either bacteriostatic or bactericidal mechanisms. These microorganisms successfully develop resistance against conventional drugs that are designed to kill or stop them from multiplying. When a fungus no longer responds to antifungal drug treatments and continues to grow, this is known as antifungal drug resistance. Bacteria have an amazing capacity to become resistant to antibiotic action as well, and the effectiveness of the scarce antifungal arsenal is jeopardised by this antibiotic resistance, which poses a severe threat to public health.

Antifungal resistance is a growing concern as it poses a significant threat to public health. Fungal infections are a significant cause of morbidity and mortality, especially in immunocompromised individuals. The limited number of antifungal agents and the emergence of resistance have led to a critical need to understand the mechanisms of antifungal drug resistance. This review provides an overview of the importance of antifungal resistance, the classes of antifungal agents, and their mode of action. It highlights the molecular mechanisms of antifungal drug resistance, including alterations in drug modification, activation, and availability. In addition, the review discusses the response to drugs via the regulation of multidrug efflux systems and antifungal drug–target interactions. We emphasize the importance of understanding the molecular mechanisms of antifungal drug resistance to develop effective strategies to combat the emergence of resistance and highlight the need for continued research to identify new targets for antifungal drug development and explore alternative therapeutic options to overcome resistance. Overall, an understanding of antifungal drug resistance and its mechanisms will be indispensable for the field of antifungal drug development and clinical management of fungal infections. [ABSTRACT FROM AUTHOR]

The ability of dermatophytes to live in communities and resist antifungal drugs may explain treatment recurrence, especially in onychomycosis. Therefore, new molecules with reduced toxicity that target dermatophyte biofilms should be investigated. This study evaluated nonyl 3,4-dihydroxybenzoate (nonyl) susceptibility and mechanism of action on planktonic cells and biofilms of T. rubrum and T. mentagrophytes. Metabolic activities, ergosterol, and reactive oxygen species (ROS) were quantified, and the expression of genes encoding ergosterol was determined by real-time PCR. The effects on the biofilm structure were visualized using confocal electron microscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). T. rubrum and T. mentagrophytes biofilms were susceptible to nonyl and resistant to fluconazole, griseofulvin (all strains), and terbinafine (two strains). The SEM results revealed that nonyl groups seriously damaged the biofilms, whereas synthetic drugs caused little or no damage and, in some cases, stimulated the development of resistance structures. Confocal microscopy showed a drastic reduction in biofilm thickness, and transmission electron microscopy results indicated that the compound promoted the derangement and formation of pores in the plasma membrane. Biochemical and molecular assays indicated that fungal membrane ergosterol is a nonyl target. These findings show that nonyl 3,4-dihydroxybenzoate is a promising antifungal compound. [ABSTRACT FROM AUTHOR]

The use of antifungal drugs started in the 1950s with polyenes nystatin, natamycin and amphotericin B-deoxycholate (AmB). Until the present day, AmB has been considered to be a hallmark in the treatment of invasive systemic fungal infections. Nevertheless, the success and the use of AmB were associated with severe adverse effects which stimulated the development of new antifungal drugs such as azoles, pyrimidine antimetabolite, mitotic inhibitors, allylamines and echinochandins. However, all of these drugs presented one or more limitations associated with adverse reactions, administration route and more recently the development of resistance. To worsen this scenario, there has been an increase in fungal infections, especially in invasive systemic fungal infections that are particularly difficult to diagnose and treat. In 2022, the World Health Organization (WHO) published the first fungal priority pathogens list, alerting people to the increased incidence of invasive systemic fungal infections and to the associated risk of mortality/morbidity. The report also emphasized the need to rationally use existing drugs and develop new drugs. In this review, we performed an overview of the history of antifungals and their classification, mechanism of action, pharmacokinetic/pharmacodynamic (PK/PD) characteristics and clinical applications. In parallel, we also addressed the contribution of fungi biology and genetics to the development of resistance to antifungal drugs. Considering that drug effectiveness also depends on the mammalian host, we provide an overview on the roles of therapeutic drug monitoring and pharmacogenomics as means to improve the outcome, prevent/reduce antifungal toxicity and prevent the emergence of antifungal resistance. Finally, we present the new antifungals and their main characteristics. [ABSTRACT FROM AUTHOR]

Introduction: Patients undergoing cancer treatment by radiation therapy commonly develop Candida albicans infections (candidiasis). Such infections are generally treated by antifungals that unfortunately also induce numerous secondary effects in the patient. Additional to the effect on the immune system, ionizing radiation influences the vital activity of C. albicans cells themselves; however, the reaction of C. albicans to ionizing radiation acting simultaneously with antifungals is much less well documented. In this study, we explored the effects of ionizing radiation and an antifungal drug and their combined effect on C. albicans. Methods: The study essentially relied on a novel technique, referred to as optical nanomotion detection (ONMD) that monitors the viability and metabolic activity of the yeast cells in a label and attachment-free manner. Results and discussion: Our findings demonstrate that after exposure to X-ray radiation alone or in combination with fluconazole, low-frequency nanoscale oscillations of whole cells are suppressed and the nanomotion rate depends on the phase of the cell cycle, absorbed dose, fluconazole concentration, and post-irradiation period. In a further development, the ONMD method can help in rapidly determining the sensitivity of C. albicans to antifungals and the individual concentration of antifungals in cancer patients undergoing radiation therapy. [ABSTRACT FROM AUTHOR]

Introduction: Candida albicans is a prevalent opportunistic human fungal pathogen. However, there are currently very few antifungal treatments available. Inositol phosphoryl ceramide synthase is an essential and fungal-specific protein that also provides a novel and promising antifungal target. Aureobasidin A is a widely used inhibitor of inositol phosphoryl ceramide synthase, however the mechanism of resistance to aureobasidin A is largely unknown in pathogenic fungi. Methods: Here we investigated how C. albicans adapted to low and high concentrations of aureobasidin A. Results and discussions: We identified trisomy of chromosome 1 as the predominant mechanism of rapid adaptation. Resistance to aureobasidin A was unstable because of the inherent instability of aneuploids. Importantly, chromosome 1 trisomy simultaneously regulated genes which were associated with aureobasidin A resistance that are on this aneuploid chromosome as well as on other chromosomes. Furthermore, the pleiotropic effect of aneuploidy caused altered resistance not only to aureobasidin A but also to other antifungal drugs including caspofungin and 5-flucytosine. We posit aneuploidy provides a rapid and reversible mechanism of development of drug resistance and cross resistance in C. albicans. [ABSTRACT FROM AUTHOR]

The yeasts Cryptococcus albidus (Naganishia albida) usually occur on natural substrates and rarely are the etiological factor of different mycoses. More than a half of mycosis cases described in the literature were reported during the period from 2004 to 2021. In this regard, evaluation of yeast sensitivity to antimycotic drugs is as important as their identification. In the present study, two yeast isolates from the skin of female patients (age 7 and 74 years) with infective dermatitis (ICD-10-CM Code L30.3) were studied. Common identification of the isolates, MALDI-TOF mass spectrometry, and analysis of the nucleotide sequences of the ITS1-5.8S-ITS2 rDNA region showed that they belong to the species N. albida. The sensitivity of the obtained strains to antimycotics of three different chemical groups, namely itraconazole, naftifine, and amphotericin B, determined by microdilution method in a synthetic medium showed the following minimum inhibitory concentrations: 64-128, 16, and 0.125-4 μg/ml, respectively. It was found that the sensitivity of this yeast to pooled human serum was 30-47%, i.e. lower by 1.9-2.9 times than the sensitivity of the collection strains of C. albicans and C. neoformans. This result could be explained by lower prevalence of N. albida in the human population in comparison with these species. However, the sensitivity of N. albida strains to the low-molecular-weight fraction of serum was approximately the same as in C. albicans and C. neoformans, which indicates their high sensitivity to antimicrobial peptides. [ABSTRACT FROM AUTHOR]

After candidiasis and aspergillosis, mucormycosis is an opportunistic deep fungal infection that comes in third place. It is brought on by a Mucorales order angioinvasive fungus. The hallmark symptoms of this illness, which causes rapid progression, are tissue necrosis brought on by blood vessel invasion and subsequent thrombosis. Rhinocerebral mucormycosis is the most prevalent type of this condition in the maxillofacial region, affecting the oral cavity, maxilla, palate, nose, paranasal sinuses, orbits, and central nervous system extensively. The treatment of mucormycosis is mainly based on antifungal and surgical debridement. The increase of ketoacidosis in diabetics, transfusion of hematopoietic growth factors in long-term neutropenia and hyperbaric oxygen therapy may be useful. Morbidity and mortality of mucormycosis are high due to the invasive nature of the frequent underlying malignancy, hence the importance of early and appropriate management .Impairment of senses, such as taste, smell, and hearing, along with functional disabilities and compromised esthetics, promotes a negative impact on the patient after surgical debridement and maxillectomy. It adversely affects not only function and aesthetics but also results in emotional disturbances. [ABSTRACT FROM AUTHOR]

Coccidioidomycosis (Valley fever) is a fungal disease caused by the inhalation of Coccidioides posadasii or C. immitis. This neglected disease occurs in the desert areas of the western United States, most notably in California and Arizona, where infections continue to rise. Clinically, coccidioidomycosis ranges from asymptomatic to severe pulmonary disease and can disseminate to the brain, skin, bones, and elsewhere. New estimates suggest as many as 350,000 new cases of coccidioidomycosis occur in the United States each year. Thus, there is an urgent need for the development of a vaccine and new therapeutic drugs against Coccidioides infection. In this review, we discuss the battle against Coccidioides including the development of potential vaccines, the quest for new therapeutic drugs, and our current understanding of the protective host immune response to Coccidioides infection.

Introduction: The presence of Candida in urine, called Candiduria. Immunocompromised individuals are more susceptible to this infection and it can cause life-threatening complications. Candida albicans is most common isolate in Urinary Tract Infections (UTI) but in recent years this is shifting to non-albicans groups. Researchers found that azole is the drug of choice against Candida infections but due to excess use of these drugs resistance is developing more frequently for azole group drugs and drug resistant isolates are increasing gradually. A unique virulence factor i.e biofilm production, similarly like bacterial species is a crucial factor which contributes to the resistance against antifungal drugs. Aim: To assess the prevalence of Candida spp. in UTI retrospectively. Materials and Methods: The present retrospective study was conducted in Department of Microbiology, T.S Misra Medical College, Lucknow, Uttar-Pradesh, India from January 2018 to February 2020. A total of 1576 urine samples were collected from different wards of hospitals and Intensive Care Unit (ICU) with age group 0-80 years. Out of 1576 urine samples received, 786 had fungal growth, from which 176 Candida spp. were isolated. Candidauria and Candida UTIs data were collected from Institute's microbiology records retrospectively. The obtained results were statistically analysed in numbers and percentages using MS Excel 2013 version. Result: The prevalence of Candida species was 11.2%. The age group between 21-30 years was more prevalent. Diabetes mellitus was the main co-morbidity factor in Candiduria patients. The incidence rate was high in ICU patients 161 (91.5%) than non ICU patients (8.5%). Most the samples were isolated from general medicine (45.3%) and Obstetrics and Gynaecology department (34.8%) followed by general surgery (15.5%) and pediatric department (4.4%). Conclusion: Present study found the high prevalence of candiduria and the isolates were biofilm producers with increasing resistance against most common drugs fluconazole which is a major concern for the treatment and management aspects. In immunocompromised patients, it is important to identify the species of Candida isolates as well as their antifungal susceptibility pattern to assist the clinicians in treating the patients with candiduria

IntroductionPatients undergoing cancer treatment by radiation therapy commonly develop Candida albicans infections (candidiasis). Such infections are generally treated by antifungals that unfortunately also induce numerous secondary effects in the patient. Additional to the effect on the immune system, ionizing radiation influences the vital activity of C. albicans cells themselves; however, the reaction of C. albicans to ionizing radiation acting simultaneously with antifungals is much less well documented. In this study, we explored the effects of ionizing radiation and an antifungal drug and their combined effect on C. albicans.MethodsThe study essentially relied on a novel technique, referred to as optical nanomotion detection (ONMD) that monitors the viability and metabolic activity of the yeast cells in a label and attachment-free manner.Results and discussionOur findings demonstrate that after exposure to X-ray radiation alone or in combination with fluconazole, low-frequency nanoscale oscillations of whole cells are suppressed and the nanomotion rate depends on the phase of the cell cycle, absorbed dose, fluconazole concentration, and post-irradiation period. In a further development, the ONMD method can help in rapidly determining the sensitivity of C. albicans to antifungals and the individual concentration of antifungals in cancer patients undergoing radiation therapy.

VT-1161 is a novel tetrazole antifungal agent with high specificity for fungal CYP51 (compared to human CYP enzymes) which has been proven to have fewer adverse effects and drug–drug interaction profiles due to fewer off-target inhibitors. In this study, we evaluated the anti-biofilm potential of VT-1161 against mono- and dual-species biofilms of Candida albicans, Klebsiella pneumoniae and Staphylococcus aureus. VT-1161 inhibited planktonic growth of all three strains, with an MIC value of 2 µg mL−1 for C. albicans and 0.5 µg mL−1 for K. pneumoniae and S. aureus, and killed 99.9% of the microbial populations, indicating a cytocidal action. Additionally, VT-1161 showed an excellent anti-biofilm action, since it inhibited mono-microbial biofilms by 80% at 0.5 µg mL−1, and dual-species biofilms of C. albicans/K. pneumoniae and C. albicans/S. aureus by 90% at the same concentration. Additionally, the eradication of mature biofilms after 24 h of VT-1161 exposure was excellent, reaching 90% at 2 μg mL−1 for both mono- and dual-species biofilms. In such mixed biofilms, the use of VT-1161 was revealed to be an alternative treatment because it was able to reduce the number of cells of each species during both inhibition and eradication. Since long-term therapy is necessary for most fungal biofilm infections due to their recurrence and obstinacy, VT-1161 showed low cytotoxicity against normal human cell lines and also against the invertebrate model Caenorhabditis elegans. Considering the excellent anti-biofilm potential and its GRAS (generally recognized as safe) status, VT-1161 may find use in the prevention or therapeutic treatment of mono- or poly-microbial biofilms. [ABSTRACT FROM AUTHOR]

Infection with Aspergillus fumigatus polymycovirus 1 (AfuPmV-1) weakens resistance of Aspergillus fumigatus common reference strain Af293 biofilms in intermicrobial competition with Pseudomonas aeruginosa. We compared the sensitivity of two infected and one virus-free Af293 strains to antifungal drugs. All three were comparably sensitive to drugs affecting fungal membranes (voriconazole, amphotericin) or cell wall glucan synthesis (micafungin, caspofungin). In contrast, forming biofilms of virus-free Af293 were much more resistant than AfuPmV-1-infected Af293 to nikkomycin Z (NikZ), a drug inhibiting chitin synthase. The IC50 for NikZ on biofilms was between 3.8 and 7.5 µg/mL for virus-free Af293 and 0.94–1.88 µg/mL for infected strains. The IC50 for the virus-free A. fumigatus strain 10AF was ~2 µg/mL in most experiments. NikZ also modestly affected the planktonic growth of infected Af293 more than the virus-free strain (MIC 50%, 2 and 4 µg/mL, respectively). Virus-free Af293 biofilm showed increased metabolism, and fungus growing as biofilm or planktonically showed increased growth compared to infected; these differences do not explain the resistance of the virus-free fungus to NikZ. In summary, AfuPmV-1 infection sensitized A. fumigatus to NikZ, but did not affect response to drugs commonly used against A. fumigatus infection. Virus infection had a greater effect on NikZ inhibition of biofilm than planktonic growth. [ABSTRACT FROM AUTHOR]

Fungal infections caused by Candida species have become a constant threat to public health, especially for immunocompromised patients, who are considered susceptible to this type of opportunistic infections. Candida albicans is known as the most common etiological agent of candidiasis; however, other species, such as Candida tropicalis, Candida parapsilosis, Nakaseomyces glabrata (previously known as Candida glabrata), Candida auris, Candida guilliermondii, and Pichia kudriavzevii (previously named as Candida krusei), have also gained great importance in recent years. The increasing frequency of the isolation of this non-albicans Candida species is associated with different factors, such as constant exposure to antifungal drugs, the use of catheters in hospitalized patients, cancer, age, and geographic distribution. The main concerns for the control of these pathogens include their ability to evade the mechanisms of action of different drugs, thus developing resistance to antifungal drugs, and it has also been shown that some of these species also manage to evade the host's immunity. These biological traits make candidiasis treatment a challenging task. In this review manuscript, a detailed update of the recent literature on the six most relevant non-albicans Candida species is provided, focusing on the immune response, evasion mechanisms, and new plant-derived compounds with antifungal properties. [ABSTRACT FROM AUTHOR]

Novel agents to treat invasive fungal infections are urgently needed because the small number of established targets in pathogenic fungi makes the existing drug repertoire particularly vulnerable to the emergence of resistant strains. Recently, we reported that Candida albicans Bdf1, a bromodomain and extra‐terminal domain (BET) bromodomain with paired acetyl‐lysine (AcK) binding sites (BD1 and BD2) is essential for fungal cell growth and that an imidazopyridine (1) binds to BD2 with selectivity versus both BD1 and human BET bromodomains. Bromodomain binding pockets contain a conserved array of structural waters. Molecular dynamics simulations now reveal that one water molecule is less tightly bound to BD2 than to BD1, explaining the site selectivity of 1. This insight is useful in the performance of ligand docking studies to guide design of more effective Bdf1 inhibitors, as illustrated by the design of 10 new imidazopyridine BD2 ligands 1a–j, for which experimental binding and site selectivity data are presented. [ABSTRACT FROM AUTHOR]

Definition: Antifungal drugs prevent topical or invasive fungal infections (mycoses) either by stopping growth of fungi (termed fungistatic) or by killing the fungal cells (termed fungicidal). Antibiotics also prevent bacterial infections through either bacteriostatic or bactericidal mechanisms. These microorganisms successfully develop resistance against conventional drugs that are designed to kill or stop them from multiplying. When a fungus no longer responds to antifungal drug treatments and continues to grow, this is known as antifungal drug resistance. Bacteria have an amazing capacity to become resistant to antibiotic action as well, and the effectiveness of the scarce antifungal arsenal is jeopardised by this antibiotic resistance, which poses a severe threat to public health. [ABSTRACT FROM AUTHOR]

Nallely Nava-Pérez, Lisset G Neri-García, Oscar E Romero-González, Joshua A Terrones-Cruz, Laura C García-Carnero,* Héctor M Mora-Montes* Departamento de Biología, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato, Guanajuato, 36050, Gto., México*These authors contributed equally to this workCorrespondence: Laura C García-Carnero; Héctor M Mora-Montes, Departamento de Biología, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato, Noria Alta s/n, col. Noria Alta, C.P, Guanajuato, 36050, Gto., México, Tel +52 473-7320006 Ext. 8193, Fax +52 473-7320006 Ext. 8153, Email laura_cgc@hotmail.com; hmora@ugto.mxAbstract: Sporotrichosis is an important subcutaneous mycosis with high prevalence and threat to human and animal health worldwide. Sporothrix schenckii, Sporothrix brasiliensis, and Sporothrix globosa are the main etiological agents of this disease; and even though many efforts have been made recently to understand the Sporothrix-host interaction, little is known about S. globosa, an underestimated species. This organism shows the lowest virulence among the members of the Sporothrix pathogenic clade and represents an important pathogenic agent due to its global distribution. Here, we offer a review with all the known information about S. globosa, including its genome and proteomic information, and compare it with S. schenckii and S. brasiliensis, to explain the differences observed among these species, in terms of virulence, the host immune response, and the antifungal sensitivity. Also, we provide the gene prediction of some S. globosa putative virulence factors.Keywords: antifungal drugs, fungal infection, host–fungus interplay, epidemiology, diagnosis, treatment

Leena Abdulaziz,1 Esraa Elhadi,1,2 Ejlal A Abdallah,3 Fadlalbaseer A Alnoor,4 Bashir A Yousef5 1Department of Pharmacology, Faculty of Pharmacy, Omdurman Islamic University, Khartoum, 14415, Sudan; 2Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 3Department of Pharmacology and Pharmacy Practice, Faculty of Pharmacy, Sudan University of Science and Technology, Khartoum, 11111, Sudan; 4Department of Pharmacology, Faculty of Pharmacy, National University, Khartoum, 11111, Sudan; 5Department of Pharmacology, Faculty of Pharmacy, University of Khartoum, Khartoum, 11111, SudanCorrespondence: Bashir A Yousef, Department of Pharmacology, Faculty of Pharmacy, University of Khartoum, Al-Qasr Ave, Khartoum, 11111, Sudan, Tel +249 912932418, Fax +249 183780696, Email bashiralsiddiq@gmail.comAbstract: Drug repurposing process aims to identify new uses for the existing drugs to overcome traditional de novo drug discovery and development challenges. At the same time, as viral infections became a serious threat to humans and the viral organism itself has a high ability to mutate genetically, and due to serious adverse effects that result from antiviral drugs, there are crucial needs for the discovery of new antiviral drugs, and to identify new antiviral effects for the exciting approved drugs towards different types of viral infections depending on the observed antiviral activity in preclinical studies or clinical findings is one of the approaches to counter the viral infections problems. This narrative review article summarized mainly the published preclinical studies that evaluated the antiviral activity of drugs that are approved and used mainly as antibacterial, antifungal, antiprotozoal, and anthelmintic drugs, and the preclinical studies included the in silico, in vitro, and in vivo findings, additionally some clinical observations were also included while trying to relate them to the preclinical findings. Finally, the structure used for writing about the antiviral activity of the drugs was according to the families of the viruses used in the studies to form a better image for the target of antiviral activity of different drugs in the different kinds of viruses and to relate between the antiviral activity of the drugs against different strains of viruses within the same viral family.Keywords: drug repurposing, antiviral activity, antibacterial drugs, antifungal drugs, antiprotozoal agents, anthelmintic drugs

The increasing cases of drug resistance and high toxicity associated with the currently used antifungal agents are a worldwide public health concern. There is an urgent need to develop new antifungal drugs with unique target mechanisms. Plant-based compounds, such as carvacrol, eugenol, coumarin, cinnamaldehyde, curcumin, thymol, etc., have been explored for the development of promising antifungal agents due to their diverse biological activities, lack of toxicity, and availability. However, researchers around the world are unable to fully utilize the potential of natural products due to limitations, such as their poor bioavailability and aqueous solubility. The development of hybrid molecules containing natural products is a promising synthetic approach to overcome these limitations and control microbes’ capability to develop resistance. Based on the potential advantages of hybrid compounds containing natural products to improve antifungal activity, there have been different reported synthesized hybrid compounds. This paper reviews different literature to report the potential antifungal activities of hybrid compounds containing natural products.

The mortality rates of invasive fungal infections remain high because of the limited number of antifungal drugs available and antifungal drug resistance, which can rapidly evolve during treatment. Mutations in key resistance genes such as ERG11 were postulated to be the predominant cause of antifungal drug resistance in the clinic. However, recent advances in whole genome sequencing have revealed that there are multiple mechanisms leading to the microevolution of resistance. In many fungal species, resistance can emerge through ERG11-independent mechanisms and through the accumulation of mutations in many genes to generate a polygenic resistance phenotype. In addition, genome sequencing has revealed that full or partial aneuploidy commonly occurs in clinical or microevolved in vitro isolates to confer antifungal resistance. This review will provide an overview of the mutations known to be selected during the adaptive microevolution of antifungal drug resistance and focus on how recent advances in genome sequencing technology have enhanced our understanding of this process.

Understanding the metabolism of pharmaceutical compounds is a fundamental prerequisite for ensuring their safety and efficacy in clinical use. However, conventional methods for monitoring drug metabolism often come with the drawbacks of being time-consuming and costly. In an ongoing quest for innovative approaches, the application of electrochemistry in metabolism studies has gained prominence as a promising approach for the synthesis and analysis of drug transformation products. In this study, we investigated the hepatic metabolism of voriconazole, an antifungal medication, by utilizing human liver microsomes (HLM) assay coupled with LC-MS. Based on the obtained results, the electrochemical parameters were optimized to simulate the biotransformation reactions. Among the various electrodes tested, the chemometric analysis revealed that the iron(II) phthalocyanine electrode was the most effective in catalyzing the formation of all hepatic voriconazole metabolites. These findings exemplify the potential of phthalocyanine electrodes as an efficient and cost-effective tool for simulating the intricate metabolic processes involved in drug biotransformation, offering new possibilities in the field of pharmaceutical research. Additionally, in silico analysis showed that two detected metabolites may exhibit significantly higher acute toxicity and mutagenic potential than the parent compound.

Purpose: The objective of this study was to design and develop nanoemulsion formulations of Itraconazole (ITZ), a water-insoluble, potent antifungal drug using the spontaneous emulsification method, to improve the ocular delivery and achieve a sustained release of the drug. Methods: The oil was selected on the basis of the ITZ solubility while the surfactant and co-surfactant were selected based on the thermodynamic stability and globule size. Following the selection of components, a pseudo-ternary phase diagram was constructed for the most promising formulation (F11) using benzyl benzoate (BB) as the oil, Eumulgin CO40 as the surfactant, and propylene glycol as the co-surfactant, by the design of experiments (DoE). Results: F7 and F11 formulations were found to have an average globule size of 223.5 ± 10.7 nm and 157.5 ± 14.2 nm, besides thermodynamic stability and suitable physicochemical properties. F11 possessed an almost seven-fold higher cumulative percentage of in vitro released ITZ, in comparison to ITZ aqueous suspension after 24 hours. The release data suggested that the best fitted kinetical model for F11 and F7 was the Higuchi and Korsmeyer-Peppas model. Conclusion: The extended-release of the drug beside an acceptable amount of loaded ITZ suggested that nanoemulsion is suitable for the delivery of the ITZ.

Biological networks are characterized by diverse interactions and dynamics in time and space. Many regulatory modules operate in parallel and are interconnected with each other. Some pathways are functionally known and annotated accordingly, e.g., endocytosis, migration, or cytoskeletal rearrangement. However, many interactions are not so well characterized. For reconstructing the biological complexity in cellular networks, we combine here existing experimentally confirmed and analyzed interactions with a protein-interaction inference framework using as basis experimentally confirmed interactions from other organisms. Prediction scoring includes sequence similarity, evolutionary conservation of interactions, the coexistence of interactions in the same pathway, orthology as well as structure similarity to rank and compare inferred interactions. We exemplify our inference method by studying host-pathogen interactions during infection of Mus musculus (phagolysosomes in alveolar macrophages) with Aspergillus fumigatus (conidia, airborne, asexual spores). Three of nine predicted critical host-pathogen interactions could even be confirmed by direct experiments. Moreover, we suggest drugs that manipulate the host-pathogen interaction.

Mucormycosis is a fungal infection caused by members of Mucorales and zygomycotic species. These are saprophytes known as Mucormycotina that grow from rotten matter or soils during the decomposition of soil. It has been seen affecting many COVID-19-affected patients recently in India. Mucormycosis can be diagnosed in six different sites depending on the immunological status and the site of the body affected. The six manifestations are rhinocerebral, pulmonary, cutaneous, gastrointestinal, and central nervous system or disseminated forms. Here, we present a dental case of mucormycosis or black fungus disease that has affected an immune-compromised patient who had suffered from COVID-19 2 months ago. Surgical debridement was done and the histopathologic study revealed fungal hyphae. Systemic antifungal therapy was administered that helped the patient to recover in 7-week time.

Niosomes have potential applications in topical drug delivery system. Niosomes play an increasingly important role in drug delivery as they can reduce toxicity and modify pharmacokinetic and bio)availability. Topically applied niosomes can increase the residence time of drugs in the stratum corneum and epidermis, while reducing the systemic absorption of the drug. It can act as drug containing reservoirs and the modification of the vesicular compositions or surface properties can adjust the drug release rate and the affinity for the target site. Luliconazole is a potential prescription candidate drug for the treatment of topical fungal infections. However, it has water solubility and skin permeability limitations. To overcome these limitations, a niosomal gel of luliconazole was formulated using Span 60, cholesterol and chloroform to improve its bioavailability and to reduce its toxicity. Niosomes were analyzed by transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR) for morphological and spectral studies respectively. The formulations had ideal nanometric vesicle sizes, encapsulation efficiency (88.891% ± 0.0364%), Zeta potential (-40.1 mV), and storage instability was not observed. The sustained-release profile of niosomal gel was observed for up to 24 h. The highest R² value was 0.913; the Higuchi model was considered the best fit model for the niosomal formulations. Based on the results, it can be concluded that niosomal luliconazole may enhance the activity of luliconazole against Candida albicans. [ABSTRACT FROM AUTHOR]

Introduction: The increased incidence and preponderance of dermatomycosis cause the issue of determining antimycotic agents of systemic and external action to be particularly pertinent, considering the etiology, clinical form, and majority of mycoses, the sensitivity of pathogens to them, and the existence of concurrent conditions. The study aims to analyze the etiology, pathogenesis, and diagnosis of dermatomycosis of the scalp, nails, feet, hands, smooth skin, and inguinal dermatophytosis. Patients and methods: To meet the aim of the study, it is attempted to generate an algorithm for pharmaceutical counseling of patients suffering from various types of dermatomycosis. Over the span of five months, a survey was carried out of 25 visitors to the pharmacy with a diagnosis of dermatomycosis. Results: Based on the results, it was revealed that most of the visitors suffer from dermatomycosis of the feet - 10 people (40%), the second in terms of incidence is onychomycosis - 5 people (19%), the third in terms of incidence is dermatomycosis of the groin area - 4 people (15%), the fourth in the incidence is dermatomycosis of the scalp - 4 people (14%). Conclusion: To treat different types of dermatomycosis, various antifungal drugs in different dosage forms can be used. For each type of disease, a specific course of treatment is selected. The duration of the course of treatment depends on the skin lesion area, the duration of the disease, and the presence of complications. [ABSTRACT FROM AUTHOR]

Introduction: In clinical Otorhinolaryngology practice, Otomycosis is a common problem to overcome caused by Aspergillus and Candida species. Although we come across many difficulties to diagnose and treat otomycosis infections, many patients show drug resistance to antifungal agents with a high prevalence rate. Aim: To elucidate the pattern of mycological agents and susceptibility testing of fungal species in samples collected from patients with an ear infection at a tertiary hospital. Materials and Methods: The present study was a hospital-based cross-sectional study conducted in the Department of Microbiology and Department of Ear, Nose, and Throat (ENT) at Aarupadai Veedu Medical College and Hospital, Puducherry, India from August 2018 to January 2020. A total of 126 samples were collected, transported, and analysed for bacteriological and mycological analysis using direct inspection and culture techniques. By using the disc diffusion technique, the antifungal susceptibility testing was carried out to determine the sensitivity and resistance against ketoconazole, itraconazole, fluconazole, and Amphotericin B. Data were analysed in terms of frequency using the Statistical Package for the Social Sciences (SPSS) software 25.0 version. Results: Out of 126 samples, fungal isolates were 92, out of which the most common fungal isolate was Aspergillus niger followed by A. flavus, Candida albicans (C. albicans), A. terreus, and A. fumigatus. Also, the major common bacterial isolates were Staphylococcus aureus followed by Pseudomonas, Proteus, Escherichia coli (E. coli), and Klebsiella spp. Prevalence in males (58.73%) was more as compared to the females (41.27%), and itching was the most common presenting symptom. Otomycosis in Chronic Suppurative Otitis Media (CSOM) mainly affected males (40%) and is common in middle-aged groups (20-35 years) of outdoor and indoor workers, housewives, and farmers, particularly during the monsoon season. Antifungal susceptibility testing of A. flavus and A. niger isolates revealed high sensitivity to amphotericin B, itraconazole, and ketoconazole drugs but low efficacy to fluconazole drugs. Conclusion: Otomycosis should be suspected clinically to prevent the unnecessary use of antibiotics. A high incidence of otomycosis has been encountered in many tropical countries. In present study, Aspergillus spp. and Candida spp. were the commonest fungal isolates in otomycosis. In our community currently, two drugs, amphotericin B, and ketoconazole are the most frequently used for fungal infection. Properly identifying fungal agents and host factors involved in otomycosis can improve such patients' outcomes. [ABSTRACT FROM AUTHOR]

Invasive fungal diseases (IFDs) are a relevant cause of morbidity and mortality in children with cancer. Their correct prevention and management impact patients' outcomes. The aim of this review is to highlight the rationale and novel insights into antifungal prophylaxis and treatment in pediatric patients with oncological and hematological diseases. The literature analysis showed that IFDs represent a minority of cases in comparison to bacterial and viral infections, but their impact might be far more serious, especially when prolonged antifungal therapy or invasive surgical treatments are required to eradicate colonization. A personalized approach is recommended since pediatric patients with cancer often present with different complications and require tailored therapy. Moreover, while the Aspergillus infection rate does not seem to increase, in the near future, new therapeutic recommendations should be required in light of new epidemiological data on Candidemia due to resistant species. Finally, further studies on CAR-T treatment and other immunotherapies are needed in patients with unique needs and the risk of complications. Definitive guidelines on IFD treatment considering the evolving epidemiology of antifungal resistance, new therapeutic approaches in pediatric cancer, novel antifungal drugs and the importance of an appropriate antifungal stewardship are urgently needed. [ABSTRACT FROM AUTHOR]

Combination antifungal therapy is widely used but not well understood. We analyzed the spectrophotometric readings from a multicenter study conducted by the New York State Department of Health to further characterize the in vitro interactions of the major classes of antifungal agents against Candida spp. Loewe additivity-based fractional inhibitory concentration index (FICi) analysis and Bliss independence-based response surface (BIRS) analysis were used to analyze two-drug inter- and intraclass combinations of triazoles (AZO) (voriconazole, posaconazole), echinocandins (ECH) (caspofungin, micafungin, anidulafungin), and a polyene (amphotericin B) against Candida albicans, C. parapsilosis, and C. glabrata. Although mean FIC indices did not differ statistically significantly from the additivity range of 0.5–4, indicating no significant pharmacodynamic interactions for all of the strain–combinations tested, BIRS analysis showed that significant pharmacodynamic interactions with the sum of percentages of interactions determined with this analysis were strongly associated with the FIC indices (Χ2 646, p < 0.0001). Using a narrower additivity range of 1–2 FIC index analysis, statistically significant pharmacodynamic interactions were also found with FICi and were in agreement with those found with BIRS analysis. All ECH+AB combinations were found to be synergistic against all Candida strains except C. glabrata. For the AZO+AB combinations, synergy was found mostly with the POS+AB combination. All AZO+ECH combinations except POS+CAS were synergistic against all Candida strains although with variable magnitude; significant antagonism was found for the POS+MIF combination against C. albicans. The AZO+AZO combination was additive for all strains except for a C. parapsilosis strain for which antagonism was also observed. The ECH+ECH combinations were synergistic for all Candida strains except C. glabrata for which they were additive; no antagonism was found. [ABSTRACT FROM AUTHOR]

Eight genetically distinct families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) were described in organisms allover the phylogenetic tree. They catalyze the hydration of CO 2 to bicarbonate and protons, and are involved in pH regulation, chemosensing and metabolism. The 15 α-CA isoforms present in humans are pharmacological drug targets known for decades, their inhibitors being used as diuretics, antiglaucoma, antiepileptic or antiobesity drugs, as well as for the management of acute mountain sickness, idiopathic intracranial hypertension and recently, as antitumor theragnostic agents. Other potential applications include the use of CA inhibitors (CAIs) in inflammatory conditions, cerebral ischemia, neuropathic pain, or for Alzheimer's/Parkinson's disease management. CAs from pathogenic bacteria, fungi, protozoans and nematodes started to be considered as drug targets in recent years, with notable advances registered ultimately. CAIs have a complex multipharmacology probably unique to this enzyme, which has been exploited intensely but may lead to other relevant applications in the future, due to the emergence of drug design approaches which afforded highly isoform-selective compounds for most α-CAs known to date. They belong to a multitude of chemical classes (sulfonamides and isosteres, (iso)coumarins and related compounds, mono- and dithiocarbamates, selenols, ninhydrines, boronic acids, benzoxaboroles, etc). The polypharmacology of CAIs will also be discussed since drugs originally discovered for the treatment of non-CA related conditions (topiramate, zonisamide, celecoxib, pazopanib, thiazide and high-ceiling diuretics) show efective inhibition against many CAs, which led to their repurposing for diverse pharmacological applications. Significance Statement Carbonic anhydrase inhibitors have multiple pharmacologic applications as diuretics, antiglaucoma, antiepileptic, antiobesity, anti-acute mountain sickness, anti-idiopathic intracranial hypertension and as antitumor drugs. Their use in inflammatory conditions, cerebral ischemia, neuropathic pain, or neurodegenerations started to be investigated recently. Parasite carbonic anhydrases are also drug targets for antiinfectives with novel mechanisms of action which can by pass drug resistance to commonly used such agents. Drugs discovered for the management of other conditions that effectively inhibit these enzymes exert interesting polypharmacologic effects., (Copyright © 2024 American Society for Pharmacology and Experimental Therapeutics.)

Currently, fungal and bacterial skin infections rank among the most challenging public health problems due to the increasing prevalence of microorganisms and the development of resistance to available drugs. A major issue in treating these infections with conventional topical medications is the poor penetration through the stratum corneum, the outermost layer of the skin. The concept of microneedles seems to be a future-proof approach for delivering drugs directly into deeper tissues. By bypassing the skin barrier, microneedle systems allow therapeutic substances to reach deeper layers more efficiently, significantly improving treatment outcomes. Nonetheless, the primary challenges regarding the effectiveness of microneedles involve selecting the appropriate size and shape, along with polymer composition and fabrication technology, to enable controlled and efficient drug release. This review offers a comprehensive overview of the latest knowledge on microneedle types and manufacturing techniques, highlighting their potential effectiveness in treating bacterial and fungal skin infections. It includes updated statistics on infection prevalence and provides a detailed examination of common bacterial and fungal diseases, focusing on their symptoms, causative species, and treatment methods. Additionally, the review addresses safety considerations, regulatory aspects, and future perspectives for microneedle-based therapeutic systems. It also underscores the importance of industrialization and clinical translation efforts, emphasizing the significant potential of microneedle technology for advancing medical applications., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Physicians are increasingly prescribing antifungal drugs empirically to treat hospital-acquired infections quickly. This makes it obvious that fungal infections require more attention and systematic monitoring of resistance among them. The aim of the study was to identify antifungal drugs that retain their efficacy against C. albicans isolates. There were 17 clinical isolates of Candida albicans obtained from patients and tested for susceptibility to antifungal drugs using the standard double dilution method. Amphotericin B, fluconazole, itraconazole, micafungin, and posaconazole were used in the study. To determine the groups of antimycotics to which the studied microorganisms retain sensitivity, a hierarchical cluster analysis was performed using the Ward's method. The tested representatives of the genus Candida showed the lowest sensitivity to fluconazole. The efficacy of amphotericin B and itraconazole was almost at the same level. In turn, micafungin and posaconazole showed the best results against C. albicans isolates . Ward's cluster analysis combined the results of C. albicans susceptibility to fluconazole, micafungin and itraconazole by the highest mathematical similarity. Amphotericin B and posaconazole were combined into one cluster due to their better efficacy against Candida albicans isolates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Faustova, Dobrovolskyi, Loban', Bereza, Kotelnikova and Dobrovolskyi.)