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Drug Delivery Dec 2021We examined formulating a new antifungal agent, posaconazole (POS) and its derivatives, with different molecular vehicles. Several combinations of drug and carrier...
We examined formulating a new antifungal agent, posaconazole (POS) and its derivatives, with different molecular vehicles. Several combinations of drug and carrier molecules were synthesized, and their antifungal activities were evaluated against . Posaconazole and four of its derivatives were conjugated to either generation 5 (G5) dendrimers or partially modified G5 dendrimers. The antifungal activities of these compounds suggest that conjugates with specific chemical linkages showed better fungistatic activity than direct conjugates to POS. In particular, a polyethylene glycol (PEG)-imidazole modified G5 dendrimer demonstrated improved antifungal efficacy relative to the parent G5 molecule. Further studies were then conducted with POS derived molecules coupled to PEG-imidazole modified G5 dendrimers to achieve a highly soluble and active conjugate of POS. This conjugated macromolecule averaged 23 POS molecules per G5 and had a high solubility with 50 mg/mL, which improved the molar solubility of POS from less than 0.03 mg/mL to as high as 16 mg/mL in water. The primary release profile of the drug in human plasma was extended to over 72 h, which is reflected in the inhibition of growth of over 96 h. These POS-polymer conjugates appear to be novel and efficient antifungal agents.
Topics: Antifungal Agents; Aspergillus fumigatus; Chemistry, Pharmaceutical; Dendrimers; Dose-Response Relationship, Drug; Drug Carriers; Drug Liberation; Imidazoles; Nanoparticles; Polyethylene Glycols; Triazoles
PubMed: 34617850
DOI: 10.1080/10717544.2021.1986605 -
Applied Microbiology and Biotechnology Jan 2016Pimaricin (natamycin) is a small polyene macrolide antibiotic used worldwide. This efficient antimycotic and antiprotozoal agent, produced by several soil bacterial... (Review)
Review
Pimaricin (natamycin) is a small polyene macrolide antibiotic used worldwide. This efficient antimycotic and antiprotozoal agent, produced by several soil bacterial species of the genus Streptomyces, has found application in human therapy, in the food and beverage industries and as pesticide. It displays a broad spectrum of activity, targeting ergosterol but bearing a particular mode of action different to other polyene macrolides. The biosynthesis of this only antifungal agent with a GRAS status has been thoroughly studied, which has permitted the manipulation of producers to engineer the biosynthetic gene clusters in order to generate several analogues. Regulation of its production has been largely unveiled, constituting a model for other polyenes and setting the leads for optimizing the production of these valuable compounds. This review describes and discusses the molecular genetics, uses, mode of action, analogue generation, regulation and strategies for increasing pimaricin production yields.
Topics: Antifungal Agents; Biosynthetic Pathways; Biotechnology; Gene Expression Regulation, Bacterial; Humans; Natamycin; Streptomyces
PubMed: 26512010
DOI: 10.1007/s00253-015-7077-0 -
Revista Da Sociedade Brasileira de... 2023There is a consensus that the antifungal repertoire for the treatment of cryptococcal infections is limited. Standard treatment involves the administration of an... (Review)
Review
There is a consensus that the antifungal repertoire for the treatment of cryptococcal infections is limited. Standard treatment involves the administration of an antifungal drug derived from natural sources (i.e., amphotericin B) and two other drugs developed synthetically (i.e., flucytosine and fluconazole). Despite treatment, the mortality rates associated with fungal cryptococcosis are high. Amphotericin B and flucytosine are toxic, require intravenous administration, and are usually unavailable in low-income countries because of their high cost. However, fluconazole is cost-effective, widely available, and harmless with regard to its side effects. However, fluconazole is a fungistatic agent that has contributed considerably to the increase in fungal resistance and frequent relapses in patients with cryptococcal meningitis. Therefore, there is an unquestionable need to identify new alternatives or adjuvants to conventional drugs for the treatment of cryptococcosis. A potential antifungal agent should be able to kill cryptococci and "bypass" the virulence mechanism of the yeast. Furthermore, it should have fungicidal action, low toxicity, high selectivity, easily penetrate the central nervous system, and widely available. In this review, we describe cryptococcosis, its conventional therapy, and failures arising from the use of drugs traditionally considered to be the reference standard. Additionally, we present the approaches used for the discovery of new drugs to counteract cryptococcosis, ranging from the conventional screening of natural products to the inclusion of structural modifications to optimize anticryptococcal activity, as well as drug repositioning and combined therapies.
Topics: Humans; Antifungal Agents; Amphotericin B; Flucytosine; Fluconazole; Cryptococcosis; Cryptococcus neoformans
PubMed: 37493736
DOI: 10.1590/0037-8682-0121-2023 -
Expert Review of Clinical Pharmacology May 2015Posaconazole, a broad-spectrum triazole antifungal agent, is approved for the prevention of invasive aspergillosis and candidiasis in addition to the treatment of... (Review)
Review
Posaconazole, a broad-spectrum triazole antifungal agent, is approved for the prevention of invasive aspergillosis and candidiasis in addition to the treatment of oropharyngeal candidiasis. There is evidence of efficacy in the treatment and prevention of rarer, more difficult-to-treat fungal infections. Posaconazole oral suspension solution has shown limitations with respect to fasting state absorption, elevated gastrointestinal pH and increased motility. The newly approved delayed-release oral tablet and intravenous solution formulations provide an attractive treatment option by reducing interpatient variability and providing flexibility in critically ill patients. On the basis of clinical experience and further clinical studies, posaconazole was found to be a valuable pharmaceutical agent for the treatment of life-threatening fungal infections. This review will examine the development history of posaconazole and highlight the most recent advances.
Topics: Animals; Antifungal Agents; Aspergillosis; Candidiasis; Chemistry, Pharmaceutical; Critical Illness; Delayed-Action Preparations; Humans; Mycoses; Triazoles
PubMed: 25916666
DOI: 10.1586/17512433.2015.1034689 -
Current Pharmaceutical Design 2016Ciclopirox (CPX) has been used as an antifungal agent in various formulations to treat superficial fungal infection for decades. Its effectiveness and safety in... (Review)
Review
BACKGROUND
Ciclopirox (CPX) has been used as an antifungal agent in various formulations to treat superficial fungal infection for decades. Its effectiveness and safety in treatments have been demonstrated by multiple studies.
METHODS
Here we briefly summarize the pharmacological and toxicological properties of CPX as an antifungal agent, the new medical uses of CPX, as well as the correspondent molecular mechanisms.
RESULTS
Increasing evidence has demonstrated that CPX is able to inhibit tumor growth, ameliorate diabetes and its complications, prevent human immunodeficiency virus (HIV) infection, and improve age-associated cardiovascular defects. Interestingly, its antifungal activity and all those newly observed effects are more or less related to its capability of chelating iron and interfering with the related signaling pathways. Mechanistically, CPX is capable of modulating the activities of certain enzymes or signaling pathways, such as ribonucleotide reductase (RR), deoxyhypusine hydroxylase (DOHH)/eukaryotic translation initiation factor 5A (eIF5A), Wnt/β-catenin, hypoxia-inducible factor-1α (HIF-1 α)/vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 3 (VEGFR-3)/extracellular signal-regulated protein kinases 1/2, mammalian target of rapamycin, and cyclin dependent kinases (CDKs). Most of these activities are related to its chelation of iron.
CONCLUSION
CPX, as an antifungal agent, may be repositioned for treatment of cancer and other human diseases.
Topics: Anti-HIV Agents; Anti-Infective Agents; Antifungal Agents; Antineoplastic Agents; Cardiovascular System; Ciclopirox; Drug Screening Assays, Antitumor; Humans; Hypoglycemic Agents; Pyridones
PubMed: 27238364
DOI: 10.2174/1381612822666160530151209 -
Antimicrobial Agents and Chemotherapy Aug 2020The incidence of invasive fungal infections is rising due to the increase in susceptible populations. Current clinically available drugs have therapeutic limitations due...
The incidence of invasive fungal infections is rising due to the increase in susceptible populations. Current clinically available drugs have therapeutic limitations due to toxicity, a narrow spectrum of activity, and, more importantly, the consistent rise of fungal species that are intrinsically resistant or that develop resistance due to prolonged therapy. Thus, there is an urgent need for new broad-spectrum antifungal agents with low toxicity and a novel mechanism of action. We previously reported a new class of potent antifungal compounds, acylhydrazones, that target the fungal sphingolipid pathway. Based upon our initial lead molecules, ()-'-(5-bromo-2-hydroxybenzylidene)-2-methylbenzohydrazide and D13, we performed a structure-activity relationship study, synthesizing ca. 300 new compounds. Of these, 5 compounds were identified to be the most promising for further studies, based on their broad-spectrum activity and low toxicity in mammalian cells lines. Among these top 5 lead compounds, we report here the impressive activity of 2,4-dibromo-'-(5-bromo-2-hydroxybenzylidene)benzohydrazide (SB-AF-1002) in several models of systemic fungal infection. Our data show that SB-AF-1002 is efficacious and outperforms current standard-of-care drugs in models of invasive fungal infections, such as cryptococcosis, candidiasis, and aspergillosis. Specifically, animals treated with SB-AF-1002 not only survived the infection but also showed a clearing of fungal cells from key organs. Moreover, SB-AF-1002 was very effective in an aspergillosis model as a prophylactic therapy. SB-AF-1002 also displayed acceptable pharmacokinetic properties in mice, similar to those of the parent compound, D13. These results clearly indicate that our novel acylhydrazones constitute a new class of highly potent and efficacious antifungal agents which warrant further development for the treatment of invasive fungal infections.
Topics: Animals; Antifungal Agents; Aspergillosis; Candidiasis; Invasive Fungal Infections; Mice; Mycoses
PubMed: 32601165
DOI: 10.1128/AAC.00946-20 -
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 -
International Journal of Molecular... Dec 2022This study investigated whether sphingosine is effective as prophylaxis against spp. and spp. In vitro experiments showed that sphingosine is very efficacious against...
This study investigated whether sphingosine is effective as prophylaxis against spp. and spp. In vitro experiments showed that sphingosine is very efficacious against and (formerly named ). A mouse model of invasive aspergillosis showed that sphingosine exerts a prophylactic effect and that sphingosine-treated animals exhibit a strong survival advantage after infection. Furthermore, mechanistic studies showed that treatment with sphingosine leads to the early depolarization of the mitochondrial membrane potential (Δψm) and the generation of mitochondrial reactive oxygen species and to a release of cytochrome C within minutes, thereby presumably initiating apoptosis. Because of its very good tolerability and ease of application, inhaled sphingosine should be further developed as a possible prophylactic agent against pulmonary aspergillosis among severely immunocompromised patients.
Topics: Animals; Mice; Antifungal Agents; Candida; Sphingosine; Microbial Sensitivity Tests; Aspergillus
PubMed: 36555152
DOI: 10.3390/ijms232415510 -
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 -
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