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Revista Espanola de Quimioterapia :... Sep 2011Empirical antifungal therapy refers to initiation of an antifungal agent at the first possible clinical evidence of fungal infection. It is frequently recommended in... (Review)
Review
Empirical antifungal therapy refers to initiation of an antifungal agent at the first possible clinical evidence of fungal infection. It is frequently recommended in neutropenic high-risk hematological patients of invasive fungal infection in order to guarantee an early approach. An extensive review is made of therapeutic advances and scientific evidence in this setting. Specific recommendations for use and criteria for selection of antifungal agents are discussed.
Topics: Antifungal Agents; Humans; Mycoses; Neutropenia; Randomized Controlled Trials as Topic
PubMed: 21947092
DOI: No ID Found -
Drug Delivery Dec 2022Cutaneous fungal infection therapy confronts several issues concerning skin permeation in addition to drug resistance and adverse effects of conventional drugs. The...
Cutaneous fungal infection therapy confronts several issues concerning skin permeation in addition to drug resistance and adverse effects of conventional drugs. The repurposing strategy is supposed to overcome some of those therapeutic obstacles. Recently, atorvastatin (ATO) revealed antifungal activity. ATO is an antihyperlipidemic drug with pH-dependent solubility, which limits skin permeation. This study aims to improve ATO antifungal activity by encapsulation in an emulsomes (EMLs) system, which seeks to ameliorate skin penetration. Therefore, multiple factors were investigated according to the One-Factor-at-a-Time (OFAT) design to achieve the optimum formula with targeted characteristics. Minimizing particle-size and polydispersity-index, besides elevating zeta-potential (ZP) and entrapment-efficiency were the desirable responses during assessing 11 factors. The selected ATO-EMLs formula (E21) recorded 250.5 nm in particle size, polydispersity index of 0.4, ZP of -25.93 mV, and 83.12% of drug entrapped. Morphological study of E21 revealed spherical core-shell vesicles in nanosize. DSC, XRD, and FTIR were conducted to discover the physicochemical properties and confirm emulsomes formation. Optimized ATO-EMLs slowed drug release rate as only 75% of ATO was released after 72 h. Stability study recommended storage between 2 and 8 °C. The permeation study remarked a homogeneous penetration of EMLs in different skin layers. The skin irritation test revealed limited histopathological changes. The and microbiological studies demonstrated a good antifungal activity of ATO-EMLs. ATO-EMLs system improved antifungal activity as the MIC values reduced from 650 µg/mL for free ATO to 550 µg/mL for ATO-EMLs. These findings may shed light on ATO as an antifungal drug and nanosystems as a tool to support drug repurposing.
Topics: Antifungal Agents; Atorvastatin; Drug Repositioning; Skin Absorption; Skin
PubMed: 36428290
DOI: 10.1080/10717544.2022.2149898 -
Indian Pediatrics Mar 2008Voriconazole is a newer systemic antifungal agent effective against Candida and Aspergillus. There are few reports of its safe use in newborns. We report the first case...
Voriconazole is a newer systemic antifungal agent effective against Candida and Aspergillus. There are few reports of its safe use in newborns. We report the first case series of safe Voriconazole use in critically ill newborns with cardiac disease along with several other cardiac drugs without any significant drug interaction or side-effect.
Topics: Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Critical Illness; Humans; Infant, Newborn; Pyrimidines; Triazoles; Voriconazole
PubMed: 18367773
DOI: No ID Found -
Microbiology Spectrum Aug 2022Baicalein (BE) is a promising antifungal small-molecule compound with an extended antifungal spectrum, good synergy with fluconazole, and low toxicity, but its target...
Baicalein (BE) is a promising antifungal small-molecule compound with an extended antifungal spectrum, good synergy with fluconazole, and low toxicity, but its target protein and antifungal mechanism remain elusive. In this study, we found that BE can function against Candida albicans by disrupting glycolysis through targeting Eno1 and inhibiting its function. Eno1 acts as a key therapeutic target of the drug, as BE had no antifungal activity against the null mutant in a Galleria mellonella model of C. albicans infection. To investigate the mechanism of action, we solved the crystal structure of C. albicans Eno1(CaEno1) and then compared the difference between this structure and that of Eno1 from humans. The predicted primary binding site of BE on CaEno1 is between amino acids D261 and W274, with D263, S269, and K273 playing critical roles in the interaction with BE. Both positions S269 and K273 have different residues in the human Eno1 (hEno1). This finding suggests that BE may bind selectively to CaEno1, which would limit the potential for side effects in humans. Our findings demonstrate that Eno1 is a target protein of BE and thus may serve as a novel target for the development of antifungal therapeutics acting through the inhibition of glycolysis. Baicalein (BE) is a promising antifungal agent which has been well characterized, but its target protein is still undiscovered. The protein Eno1 plays a crucial role in the survival of Candida albicans. However, there are few antifungal agents which inhibit the functions of Eno1. Here, we found that BE can function against Candida albicans by disrupting glycolysis through targeting Eno1 and inhibiting its function. We further solved the crystal structure of C. albicans Eno1(CaEno1) and predicted that the primary binding site of BE on CaEno1 is between amino acids D261 and W274, with D263, S269, and K273 playing critical roles in the interaction with BE. Our findings will be helpful to get specific small-molecule inhibitors of CaEno1 and open the way for the development of new antifungal therapeutics targeted at inhibiting glycolysis.
Topics: Amino Acids; Antifungal Agents; Biomarkers, Tumor; Candida albicans; DNA-Binding Proteins; Flavanones; Fungal Proteins; Glycolysis; Humans; Microbial Sensitivity Tests; Phosphopyruvate Hydratase; Tumor Suppressor Proteins
PubMed: 35900099
DOI: 10.1128/spectrum.02085-22 -
Marine Drugs Oct 2022Chitin is a natural renewable and useful biopolymer limited by its insolubility; chemical derivatization can enhance the solubility and bioactivity of chitin. The...
Chitin is a natural renewable and useful biopolymer limited by its insolubility; chemical derivatization can enhance the solubility and bioactivity of chitin. The purpose of this study was to synthesize novel water-soluble chitin derivatives, sulfo-chitin (SCT) and sulfopropyl-chitin (SPCT), as antioxidant and antifungal agents. The target derivatives were characterized by means of elemental analysis, FTIR, 13C NMR, TGA and XRD. Furthermore, the antioxidant activity of the chitin derivatives was estimated by free radical scavenging ability (against DPPH-radical, hydroxyl-radical and superoxide-radical) and ferric reducing power. In addition, inhibitory effects against four fungi were also tested. The findings show that antioxidant abilities and antifungal properties were in order of SPCT > SCT > CT. On the basis of the results obtained, we confirmed that the introduction of sulfonated groups on the CT backbone would help improve the antioxidant and antifungal activity of CT. Moreover, its efficacy as an antioxidant and antifungal agent increased as the chain length of the substituents increased. This derivatization strategy might provide a feasible way to broaden the utilization of chitin. It is of great significance to minimize waste and realize the high-value utilization of aquatic product wastes.
Topics: Antioxidants; Antifungal Agents; Chitosan; Chitin; Fungi; Water
PubMed: 36354991
DOI: 10.3390/md20110668 -
Medical Mycology Jun 2023Immunosuppressed patients, transplant recipients, and those with acute or chronic respiratory disease are at increased risk for invasive fungal infections in Argentina....
Immunosuppressed patients, transplant recipients, and those with acute or chronic respiratory disease are at increased risk for invasive fungal infections in Argentina. Although the national public system guarantees universal access to health care for all citizens, little is known about the quality of available diagnostic and treatment armamentaria for invasive fungal infections in the country. Between June and August 2022, infectious disease clinicians from each of the 23 provinces and the Autonomous City of Buenos Aires were contacted to describe local access to fungal diagnostic tools and antifungal agents. The information collected included different aspects such as hospital characteristics, patients admitted and wards, access to diagnostic tools, estimated infection incidence, and treatment capacity. Thirty responses were collected from facilities throughout Argentina. Most institutions were governmental (77%). A mycology department was available in 83% of them. Histopathology was available in almost 93% of the sites, while automated methods and galactomannan tests were available in 57%, each; 53% of the sites had access to MALDI-TOF-MS through regional reference laboratories, and PCR was present in 20% of the sites. Susceptibility testing was available in 63% of the laboratories. Candida spp. (24%), Cryptococcus spp. (20%), Aspergillus spp. (18%), and Histoplasma spp. (16%) were described as the main pathogens. Fluconazole was the only antifungal agent available in all institutions. This was followed by amphotericin B deoxycholate (83%) and itraconazole (80%). If an antifungal agent was not available onsite, then 60% of the patients could receive adequate antifungal treatment within the first 48 h upon request. Although there are no significant differences in access to diagnostic and clinical management of invasive fungal infections among the Argentinean centres studied, national awareness-raising initiatives led by policymakers could help to improve their general availability.
Topics: Animals; Antifungal Agents; Argentina; Fluconazole; Itraconazole; Invasive Fungal Infections
PubMed: 37312404
DOI: 10.1093/mmy/myad058 -
Chembiochem : a European Journal of... Jun 2020Only a few natural products incorporating a diazeniumdiolate moiety have been isolated, and these compounds usually display a broad range of biological activities. Only...
Only a few natural products incorporating a diazeniumdiolate moiety have been isolated, and these compounds usually display a broad range of biological activities. Only recently has the first diazeniumdiolate natural product biosynthetic gene cluster been identified in Burkholderia cenocepacia H111, which produces the fungicide (-)-fragin and the signal molecule rac-valdiazen. In this study, l-valine was identified as the initial substrate of (-)-fragin biosynthesis with the aid of feeding experiments using isotopically labelled amino acid. The formation of the diazeniumdiolate was chemically studied with several proposed intermediates. Our results indicate that the functional group is formed during an early stage of the biosynthesis. Furthermore, an oxime compound was identified as a degradation product of (-)-fragin and was also observed in the crude extract of the wild-type strain. Moreover, a structure-activity relationship analysis revealed that each moiety of (-)-fragin is essential for its biological activity.
Topics: Antifungal Agents; Azo Compounds; Bacterial Proteins; Biological Products; Burkholderia cenocepacia; Genome, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Multigene Family; Oxidoreductases; Structure-Activity Relationship; Substrate Specificity; Valine
PubMed: 31945256
DOI: 10.1002/cbic.201900755 -
Biochemistry Apr 2024A major challenge currently facing medicinal chemists is designing agents that can selectively destroy drug resistant fungi and bacteria that have begun to emerge. One... (Review)
Review
A major challenge currently facing medicinal chemists is designing agents that can selectively destroy drug resistant fungi and bacteria that have begun to emerge. One factor that has been overlooked by virtually all drug discovery/development approaches is the supramolecular factor, in which aggregated forms of a drug candidate exhibit low selectivity in destroying targeted cells while the corresponding monomers exhibit high selectivity. This Perspective discusses how we were led to the supramolecular factor through fundamental studies with simple model systems, how we reasoned that the selectivity of monomers of the antifungal agent amphotericin B should be much greater than the selectivity of the corresponding aggregates, and how we confirmed this hypothesis using derivatives of amphotericin B. In a broader context, these findings provide a strong rationale for considering the supramolecular factor in the design of new drug candidates and the testing of virtually all of them.
Topics: Amphotericin B; Antifungal Agents; Fungi; Drug Design; Drug Discovery
PubMed: 38545902
DOI: 10.1021/acs.biochem.3c00721 -
ChemMedChem Jan 2021Fluorinated aryl- and heteroaryl-substituted monohydrazones displayed excellent broad-spectrum activity against various fungal strains, including a panel of clinically...
Fluorinated aryl- and heteroaryl-substituted monohydrazones displayed excellent broad-spectrum activity against various fungal strains, including a panel of clinically relevant Candida auris strains relative to a control antifungal agent, voriconazole (VRC). These monohydrazones displayed less hemolysis of murine red blood cells than that of VRC at the same concentrations, possessed fungicidal activity in a time-kill study, and exhibited no mammalian cell cytotoxicity. In addition, these monohydrazones prevented the formation of biofilms that otherwise block antibiotic effectiveness and did not trigger the development of resistance when exposed to C. auris AR Bank # 0390 over 15 passages.
Topics: Animals; Antifungal Agents; Biofilms; Candida; Cell Line; Cell Survival; Drug Resistance, Microbial; Halogenation; Hemolysis; Humans; Hydrazones; Mice; Microbial Sensitivity Tests; Structure-Activity Relationship; Voriconazole
PubMed: 33063957
DOI: 10.1002/cmdc.202000626 -
Journal of Chromatography. B,... Jan 2022Treatment of invasive fungal infections with Caspofungin is used as the first-line antifungal agents. The minimum inhibitory concentration value is a test which...
Treatment of invasive fungal infections with Caspofungin is used as the first-line antifungal agents. The minimum inhibitory concentration value is a test which indicates the degree of sensitivity of a strain regarding a drug. However, no value of minimum inhibitory concentration for caspofungin is available because very variable value is obtained. In this work, we study the link with the adsorption phenomenon of CSF previously described in literature and the lack of minimum inhibitory concentration value. A systematic study of the impact of different parameters on CSF adsorption is reported. The effect of the nature of container material, the aqueous solution pH and the organic solvent proportion was studied. In addition, the possibility of using a coating agent to minimize the adsorption was assayed and evaluated. Results obtained showed the importance of the material used during the manipulation of CSF. The use of acidic pH aqueous solution or the addition of acetonitrile or methanol proportions (50 % and 70 %, respectively) were found efficient to avoid adsorption of CSF on glassware material, which is the relevant strategy for analytical samples of caspofungin. The treatment of HPLC glass vials and 96-well plates with N-(2-aminoethyl)-3-aminopropyltrimethoxysilane reduced the adsorption. The significant adsorption observed in this work especially with plastic materials, questions the results obtained before in different assays and explained the absence of MIC value.
Topics: Adsorption; Antifungal Agents; Caspofungin; Chromatography, High Pressure Liquid; Glass; Microbial Sensitivity Tests; Plastics
PubMed: 34847516
DOI: 10.1016/j.jchromb.2021.123060