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Molecules (Basel, Switzerland) Apr 2023The 1,2,3-dithiazole is an underappreciated scaffold in medicinal chemistry despite possessing a wide variety of nascent pharmacological activities. The scaffold has a... (Review)
Review
The 1,2,3-dithiazole is an underappreciated scaffold in medicinal chemistry despite possessing a wide variety of nascent pharmacological activities. The scaffold has a potential wealth of opportunities within these activities and further afield. The 1,2,3-dithiazole scaffold has already been reported as an antifungal, herbicide, antibacterial, anticancer agent, antiviral, antifibrotic, and is a melanin and Arabidopsis gibberellin 2-oxidase inhibitor. These structure activity relationships are discussed in detail, along with insights and future directions. The review also highlights selected synthetic strategies developed towards the 1,2,3-dithiazole scaffold, how these are integrated to accessibility of chemical space, and to the prism of current and future biological activities.
Topics: Structure-Activity Relationship; Anti-Bacterial Agents; Antiviral Agents; Antifungal Agents; Melanins
PubMed: 37049953
DOI: 10.3390/molecules28073193 -
Drugs Jun 2014Invasive fungal disease (IFD) remains life threatening in premature infants and immunocompromised children despite the recent development of new antifungal agents.... (Review)
Review
Invasive fungal disease (IFD) remains life threatening in premature infants and immunocompromised children despite the recent development of new antifungal agents. Optimal dosing of antifungals is one of the few factors clinicians can control to improve outcomes of IFD. However, dosing in children cannot be extrapolated from adult data because IFD pathophysiology, immune response, and drug disposition differ from adults. We critically examined the literature on pharmacokinetics (PK) and pharmacodynamics (PD) of antifungal agents and highlight recent developments in treating pediatric IFD. To match adult exposure in pediatric patients, dosing adjustment is necessary for almost all antifungals. In young infants, the maturation of renal and metabolic functions occurs rapidly and can significantly influence drug exposure. Fluconazole clearance doubles from birth to 28 days of life and, beyond the neonatal period, agents such as fluconazole, voriconazole, and micafungin require higher dosing than in adults because of faster clearance in children. As a result, dosing recommendations are specific to bracketed ranges of age. PD principles of antifungals mostly rely on in vitro and in vivo models but very few PD studies specifically address IFD in children. The exposure-response relationship may differ in younger children compared with adults, especially in infants with invasive candidiasis who are at higher risk of disseminated disease and meningoencephalitis, and by extension severe neurodevelopmental impairment. Micafungin is the only antifungal agent for which a specific target of exposure was proposed based on a neonatal hematogenous Candida meningoencephalitis animal model. In this review, we found that pediatric data on drug disposition of newer triazoles and echinocandins are lacking, dosing of older antifungals such as fluconazole and amphotericin B products still need optimization in young infants, and that target PK/PD indices need to be clinically validated for almost all antifungals in children. A better understanding of age-specific PK and PD of new antifungals in infants and children will help improve clinical outcomes of IFD by informing dosing and identifying future research areas.
Topics: Adult; Age Factors; Animals; Antifungal Agents; Child; Child, Preschool; Dose-Response Relationship, Drug; Humans; Immunocompromised Host; Infant; Infant, Newborn; Infant, Premature; Models, Biological; Mycoses
PubMed: 24872147
DOI: 10.1007/s40265-014-0227-3 -
International Journal of Molecular... Feb 2023Antibiotic and antifungal resistance problems have been prevalent in recent decades. One of the efforts to solve the problems is to develop new medicines with more...
Antibiotic and antifungal resistance problems have been prevalent in recent decades. One of the efforts to solve the problems is to develop new medicines with more potent antibacterial and antifungal activity. -phenylbenzamides have the potential to be developed as antibacterial and antifungal medicine. This study aimed to synthesize -phenylbenzamides and evaluate their in silico and in vitro antibacterial and antifungal activities. The in silico studies conducted absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions along with molecular docking studies. ADMET predictions used pkCSM software online, while the docking studies used MVD software (Molegro Virtual Docker version 5.5) on Aminoglycosid-2 ″-phosphotransferase-IIa (APH2 ″-IIa) enzyme with protein data bank (PDB) ID code 3HAV as antibacterial and aspartic proteinases enzyme (Saps) with PDB ID code 2QZX as an antifungal. In vitro, antibacterial and antifungal tests were carried out using the zone of inhibition (ZOI) method. The five -phenylbenzamides (-) were successfully synthesized with a high yield. Based on in silico and in vitro studies, compounds - have antibacterial and antifungal activities, where they can inhibit the growth of Gram-positive bacteria (), Gram-negative (), and . Therefore, compounds - can be developed as a topical antibacterial and antifungal agent.
Topics: Antifungal Agents; Molecular Docking Simulation; Structure-Activity Relationship; Microbial Sensitivity Tests; Anti-Bacterial Agents
PubMed: 36769066
DOI: 10.3390/ijms24032745 -
Clinical Medicine & Research Sep 2008Voriconazole is a broad-spectrum triazole antifungal agent indicated for invasive aspergillosis, refractory Candida infections, and other emerging invasive fungal...
Voriconazole is a broad-spectrum triazole antifungal agent indicated for invasive aspergillosis, refractory Candida infections, and other emerging invasive fungal infections. Adverse cutaneous reactions associated with voriconazole therapy occur in fewer than 10% of treated patients and range from mild erythematous eruptions to life-threatening reactions such as the Stevens-Johnson syndrome and toxic epidermal necrolysis. Photosensitivity reactions are an uncommon but characteristic dermatitis in voriconazole recipients, particularly following chronic administration. We report a case of voriconazole-induced phototoxicity in a 50-year-old male with Candida parapsilosis endocarditis that reversed on discontinuation of the drug.
Topics: Antifungal Agents; Candidiasis; Endocarditis; Humans; Male; Middle Aged; Photosensitivity Disorders; Pyrimidines; Triazoles; Voriconazole
PubMed: 18801950
DOI: 10.3121/cmr.2008.806 -
Drug Design, Development and Therapy 2021The resistance of to traditional antifungal drugs brings a great challenge to clinical treatment. To overcome the resistance, developing antifungal agent sensitizers...
PURPOSE
The resistance of to traditional antifungal drugs brings a great challenge to clinical treatment. To overcome the resistance, developing antifungal agent sensitizers has attracted considerable attention. This study aimed to determine the anti- activity of BEH alone or BEH-FLC combination and to explore the underlying mechanisms.
MATERIALS AND METHODS
In vitro antifungal effects were performed by broth microdilution assay and XTT reduction assay. Infected larvae model was used to determine the antifungal effects in vivo. Probes Fluo-3/AM, FITC-VAD-FMK and rhodamine 6G were used to study the influence of BEH and FLC on intracellular calcium concentration, metacaspase activity and drug efflux of .
RESULTS
BEH alone exhibited obvious antifungal activities against . BEH plus FLC not only showed synergistic effects against planktonic cells and preformed biofilms within 8 h but also enhanced the antifungal activity in infected larvae. Mechanistic studies indicated that antifungal effects of drugs might be associated with the increasement of calcium concentration, activation of metacaspase activity to reduce virulence and anti-biofilms, but were not related to drug efflux.
CONCLUSION
BEH alone or combined with FLC displayed potent antifungal activity both in vitro and in vivo, and the underlying mechanisms were related to reduced virulence factors.
Topics: Animals; Antifungal Agents; Benserazide; Biofilms; Candida albicans; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Drug Therapy, Combination; Fluconazole; Microbial Sensitivity Tests; Moths
PubMed: 34815665
DOI: 10.2147/DDDT.S336667 -
Applied Microbiology and Biotechnology Jul 2021The morbidity and mortality caused by invasive fungal infections are increasing across the globe due to developments in transplant surgery, the use of immunosuppressive... (Review)
Review
The morbidity and mortality caused by invasive fungal infections are increasing across the globe due to developments in transplant surgery, the use of immunosuppressive agents, and the emergence of drug-resistant fungal strains, which has led to a challenge in terms of treatment due to the limitations of three classes of drugs. Hence, it is imperative to establish effective strategies to identify and design new antifungal drugs. Drug repurposing is a potential way of expanding the application of existing drugs. Recently, various existing drugs have been shown to be useful in the prevention and treatment of invasive fungi. In this review, we summarize the currently used antifungal agents. In addition, the most up-to-date information on the effectiveness of existing drugs with antifungal activity is discussed. Moreover, the antifungal mechanisms of existing drugs are highlighted. These data will provide valuable knowledge to stimulate further investigation and clinical application in this field. KEY POINTS: • Conventional antifungal agents have limitations due to the occurrence of drug-resistant strains. • Non-antifungal drugs act as antifungal agents in various ways toward different targets. • Non-antifungal drugs with antifungal activity are demonstrated as effective antifungal strategies.
Topics: Antifungal Agents; Drug Repositioning; Fungi
PubMed: 34151414
DOI: 10.1007/s00253-021-11407-7 -
IUBMB Life Aug 2017Silibinin, which is derived from Silybum marianum (milk thistle), has used as a traditional remedy for liver or biliary disorders and known to have superior antioxidant...
Silibinin, which is derived from Silybum marianum (milk thistle), has used as a traditional remedy for liver or biliary disorders and known to have superior antioxidant activity. In addition, silibinin was recently reported to have antifungal effect related to fungal apoptosis against Candida albicans and the interest in the therapeutic effect is increasing. In this study, we found another mode of antifungal action of silibinin and its antibiofilm activity on C. albicans. To investigate influence on fungal plasma membrane, propidium iodide and bis-(1, 3-dibutylbarbituric acid) trimethineoxonol [DiBAC (3)] assay were primarily carried out. After 5-h incubation with silibinin (50, 100, 150, or 200 µg/mL), the propidium iodide fluorescent percentages increased by 11.90%, 28.50%, 34.10%, and 44.52%, respectively, and the DiBAC (3) fluorescent percentages increased by 13.18%, 34.64%, 46.99%, and 57.15%, respectively. As a result, we thought that silibinin concentrations of more than 100 µg/mL have a membrane-damaging effect. Subsequently, to estimate the degree of membrane damage, we used Fluorescein isothiocyanate-labelled dextrans (FDs) of various sizes and the results indicated that silibinin allowed penetration of molecules smaller than approximately FD20 (3.3 nm). In addition, silibinin inhibited the dimorphic transition of C. albicans and resulted in the inhibition of biofilm development at an early stage. In conclusion, we found membrane-damaging effect of silibinin and its antibiofilm effect in C. albicans. © 2017 IUBMB Life, 69(8):631-637, 2017.
Topics: Antifungal Agents; Antioxidants; Apoptosis; Biofilms; Candida albicans; Candidiasis; Cell Membrane; Fluorescent Dyes; Humans; Membrane Potentials; Propidium; Silybin; Silymarin
PubMed: 28636236
DOI: 10.1002/iub.1647 -
Future Microbiology Apr 2011It has been nearly a decade since caspofungin was approved for clinical use as the first echinocandin class antifungal agent, followed by micafungin and anidulafungin.... (Review)
Review
It has been nearly a decade since caspofungin was approved for clinical use as the first echinocandin class antifungal agent, followed by micafungin and anidulafungin. The echinocandin drugs target the fungal cell wall by inhibiting the synthesis of β-1,3-D-glucan, a critical cell wall component of many pathogenic fungi. They are fungicidal for Candida spp. and fungistatic for moulds, such as Aspergillus fumigatus, where they induce abnormal morphology and growth properties. The echinocandins have a limited antifungal spectrum but are highly active against most Candida spp., including azole-resistant strains and biofilms. As they target glucan synthase, an enzyme absent in mammalian cells, the echinocandins have a favorable safety profile. They show potent MIC and epidemiological cutoff values against susceptible Candida and Aspergillus isolates, and the frequency of resistance is low. When clinical breakthrough occurs, it is associated with high MIC values and mutations in Fks subunits of glucan synthase, which can reduce the sensitivity of the enzyme to the drug by several thousand-fold. Such strains were not adequately captured by an early clinical breakpoint for susceptibility prompting a revised lower value, which addresses the FKS resistance mechanism and new pharmacokinetic/pharmacodynamic studies. Elevated MIC values unlinked to therapeutic failure can occur and result from adaptive cell behavior, which is FKS-independent and involves the molecular chaperone Hsp90 and the calcineurin pathway. Mutations in FKS1 and/or FKS2 alter the kinetic properties of glucan synthase, which reduces the relative fitness of mutant strains causing them to be less pathogenic. The echinocandin drugs also modify the cell wall architecture exposing buried glucans, which in turn induce a variety of important host immune responses. Finally, the future for glucan synthase inhibitors looks bright with the development of new orally active compounds.
Topics: Antifungal Agents; Aspergillus; Candida; Drug Resistance, Fungal; Echinocandins; Glucosyltransferases; Humans; Microbial Sensitivity Tests
PubMed: 21526945
DOI: 10.2217/fmb.11.19 -
Frontiers in Cellular and Infection... 2019There are only few drugs available to treat fungal infections, and the lack of new antifungals, along with the emergence of drug-resistant strains, results in millions...
There are only few drugs available to treat fungal infections, and the lack of new antifungals, along with the emergence of drug-resistant strains, results in millions of deaths/year. An unconventional approach to fight microbial infection is to exploit nutritional vulnerabilities of microorganism metabolism. The metal gallium can disrupt iron metabolism in bacteria and cancer cells, but it has not been tested against fungal pathogens such as and . Here, we investigate activity of gallium nitrate III [Ga(NO)] against these human pathogens, to reveal the gallium mechanism of action and understand the interaction between gallium and clinical antifungal drugs. Ga(NO) presented a fungistatic effect against azole-sensitive and -resistant strains (MIC = 32.0 mg/L) and also had a synergistic effect with caspofungin, but not with azoles and amphotericin B. Its antifungal activity seems to be reliant on iron-limiting conditions, as the presence of iron increases its MIC value and because we observed a synergistic interaction between gallium and iron chelators against . We also show that an mutant (Δ) unable to grow in the absence of iron is more susceptible to gallium, reinforcing that gallium could act by disrupting iron homeostasis. Furthermore, we demonstrate that gallium has a fungistatic effect against different species of ranging from 16.0 to 256.0 mg/L, including multidrug-resistant , and . Our findings indicate that gallium can inhibit fungal pathogens under iron-limiting conditions, showing that Ga(NO) could be a potential therapy not only against bacteria but also as an antifungal drug.
Topics: Antifungal Agents; Aspergillus fumigatus; Azoles; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Gallium; Kinetics; Microbial Sensitivity Tests
PubMed: 31921699
DOI: 10.3389/fcimb.2019.00414 -
Advanced Drug Delivery Reviews Aug 2023Nystatin is an antifungal molecule with a remarkable yet squandered versatility. In this review, its mechanism of action is explored, along with its extensive action... (Review)
Review
Nystatin is an antifungal molecule with a remarkable yet squandered versatility. In this review, its mechanism of action is explored, along with its extensive action spectrum and toxicity. A multitude of methodologies to tackle the drug's physical and chemical hurdles are outlined along with some proven-effective strategies to increase its activity and/or decrease its toxicity. A separate detailed section focused on micro and nanotechnology solutions addresses new drug delivery systems made of polymeric, metallic or lipid materials. Although the topical route depicts greater representativeness amongst these formulations, the intravenous, dental, oral, vaginal and inhalation routes are also mentioned. The unsuccessful previous attempts at developing parenteral formulations of nystatin or even the withdrawal of a nystatin-loaded multilamellar liposome should not divert research away from this drug. In fact, the interest in nystatin ought to be reawakened with the ongoing clinical trials on the promising nystatin-like genetically engineered derivate BSG005.
Topics: Humans; Antifungal Agents; Nystatin; Liposomes; Drug Delivery Systems; Polymers
PubMed: 37348678
DOI: 10.1016/j.addr.2023.114969