Two mutants selectively resistant to polyenes reveal distinct mechanisms of antifungal activity by nystatin and amphotericin B

2005 ◽  
Vol 33 (5) ◽  
pp. 1206-1209 ◽  
Author(s):  
I. Hapala ◽  
V. Klobučníková ◽  
K. Mazáňová ◽  
P. Kohút
Keyword(s):  
Antifungal Activity ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Structural Similarity ◽  
Resistant Mutant ◽  
Factors Affecting ◽  
Polyene Macrolides ◽  
Mode Of Inheritance ◽  
Nystatin Resistance

Polyene macrolides nystatin and amphotericin B are widely used in the treatment of fungal infections. In order to characterize factors affecting polyene activity, we have isolated Saccharomyces cerevisiae mutants showing selective resistance to nystatin and amphotericin B. Characterization of two of these mutants (nystatin-resistant mutant X1/16 and amphotericin B-resistant mutant X3/33) is presented. Genetic analysis revealed that resistance in each of these mutants is caused by a mutation in one gene with a different mode of inheritance. Nystatin resistance in mutant X1/16 is caused by changes in sterol spectrum while amphotericin B resistance in mutant X3/33 is probably related to modification of the cell wall. Our results suggest that, in spite of their structural similarity, nystatin and amphotericin B differ significantly in mechanisms of their antifungal activity.

Antifúngicos poliénicos. Mecanismo de acción y aplicaciones

2020 ◽  
Vol 63 (2) ◽  
pp. 7-17
Author(s):  
Evelyn Rivera-Toledo ◽  
Alan Uriel Jiménez-Delgadillo ◽  
Patricia Manzano-Gayosso
Keyword(s):  
Antifungal Activity ◽  
Key Words ◽  
Secondary Metabolism ◽  
Amphotericin B ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Variable Number ◽  
Therapeutic Failure ◽  
Morbidity And Mortality ◽  
Clinical Use

The first compounds with specific antifungal activity were identified in the middle of the last century as a product of the secondary metabolism of bacteria of the order Actinomycetales, and their clinical use significantly diminished the morbidity and mortality associated with severe fungal infections. Many of such biosynthetic compounds are characterized by a chemical polygenic structure, with a variable number of carbon-carbon double bonds. Currently, besides polygenic antimycotics, there are other antifungal agents, such as the azole compounds, that have less toxicity in patients; however, cases of therapeutic failure with such compounds have been documented, therefore, the use of polygenics is still the best alternative in such cases. This review presents data about the properties and applications of antifungal-polygenic compounds using amphotericin B as a model. Key words: Amphotericin B; antifungal polyenes; ergosterol

scholarly journals ANTI-CANDIDA ALBICANS ACTIVITY OF THE ASSOCIATION OF CITRONELAL WITH ANFOTERICIN B OR WITH CETOCONAZOLE

2019 ◽  
Vol 16 (31) ◽  
pp. 250-257
Author(s):  
Patrícia Duarte Costa SILVA ◽  
Brenda Lavínia Calixto dos SANTOS ◽  
Gustavo Lima SOARES ◽  
Wylly Araújo de OLIVEIRA
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Amphotericin B ◽  
Inhibitory Concentration ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Mortality Rates ◽  
New Drugs ◽  
High Morbidity ◽  
Isolated Species

Fungal infections caused by species of the genus Candida are responsible for high morbidity and mortality rates, mainly affecting immunocompromised individuals. Among fungi, Candida albicans is the most frequently isolated species of clinical specimens. A problem associated with increased resistance of pathogenic fungi to the agents used in the therapeutic regimen and the limited number of drugs to cure these infections. As a result, the search for new drugs with antifungal activity has become increasingly important. The aim of this study is to study the antifungal activity of citronellal alone and in combination with amphotericin B or ketoconazole. The Minimal Inhibitory Concentration of citronellal, amphotericin B and ketoconazole against strains of Candida albicans were evaluated by the microdilution technique, and the Minimum Fungicide Concentration of citronellal against the same strains was also performed. Through the checkerboard methodology the effect of the combination of citronelal with amphotericin B or with ketoconazole was determined. This study showed that the association of citronellal with ketoconazole was shown to be an additive against one of the strains of C. albicans and indifferent to another strain. While the combined activity of citronellal and amphotericin B demonstrated an indifferent effect on the strains tested.

Pharmacokinetics of Antifungal Agents

1993 ◽  
Vol 13 (2_suppl) ◽  
pp. 380-382 ◽  
Author(s):  
A. Fabris ◽  
M. V. Pellanda ◽  
C. Gardin ◽  
A. Contestabile ◽  
R. Bolzonella
Keyword(s):  
Abdominal Pain ◽  
Antifungal Activity ◽  
Amphotericin B ◽  
Peritoneal Fluid ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Intraperitoneal Administration ◽  
Point Of View ◽  
Severe Abdominal Pain ◽  
Fungal Peritonitis

The authors have evaluated the pharmacokinetics of four antifungal agents used in the therapy of fungal peritonitis. Amphotericin B (Amph B) poorly diffuses from blood into peritoneal fluid, which Intraperitoneal administration induces severe abdominal pain. 5-Fluorocytosine (5FC) easily crosses peritoneum, but resistance may appear when the drug is used alone. Ketoconazole (K) poorly penetrates into peritoneal fluid, while Fluconazole (F), used per os or intraperitoneally, shows a good antifungal activity both in serum and In the peritoneal fluid. In conclusion, from a pharmacokinetic point of view, all the antifungal agents examined, perhaps with the exception of F, do not offer, when used alone, sufficient guarantees In curing peritonitis. Therefore, for treating fungal infections in CAPD, drug combinations such as AmphB + 5FC, K + 5FC or 5FC + F have to be used.

scholarly journals Amphotericin B-conjugated polypeptide hydrogels as a novel innovative strategy for fungal infections

2018 ◽  
Vol 5 (3) ◽  
pp. 171814 ◽  
Author(s):  
Chang Shu ◽  
Tengfei Li ◽  
Wen Yang ◽  
Duo Li ◽  
Shunli Ji ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Antifungal Activity ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Water Soluble ◽  
Naphthalene Acetic Acid ◽  
Innovative Strategy ◽  
Molecular Arrangement

The present work is focused on the design and development of novel amphotericin B (AmB)-conjugated biocompatible and biodegradable polypeptide hydrogels to improve the antifungal activity. Using three kinds of promoting self-assembly groups (2-naphthalene acetic acid (Nap), naproxen (Npx) and dexamethasone (Dex)) and polypeptide sequence (Phe-Phe-Asp-Lys-Tyr, FFDKY), we successfully synthesized the Nap-FFDK(AmB)Y gels, Npx-FFDK(AmB)Y gels and Dex-FFDK(AmB)Y gels. The AmB-conjugated hydrogelators are highly soluble in different aqueous solutions. The cryo-transmission electron microscopy and scanning electron microscopy micrographs of hydrogels afford nanofibres with a width of 20–50 nm. Powder X-ray diffraction analyses demonstrate that the crystalline structures of the AmB and Dex are changed into amorphous structures after the formation of hydrogels. Circular dichroism spectra of the solution of blank carriers and the corresponding drug deliveries further help elucidate the molecular arrangement in gel phase, indicating the existence of turn features. The in vitro drug releases suggest that the AmB-conjugated hydrogels are suitable as drug-controlled release vehicles for hydrophobic drugs. The antifungal effect of AmB-conjugated hydrogels significantly exhibits the antifungal activity against Candida albicans . The results of the present study indicated that the AmB-conjugated hydrogels are suitable carriers for poorly water soluble drugs and for enhancement of therapeutic efficacy of antifungal drugs.

scholarly journals Evaluation of bisphenylthiazoles as a promising class for combating multidrug-resistant fungal infections

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0258465
Author(s):  
Mohamed Hagras ◽  
Nader S. Abutaleb ◽  
Ahmed M. Sayed ◽  
Ehab A. Salama ◽  
Mohamed N. Seleem ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Antifungal Activity ◽  
Amphotericin B ◽  
Antifungal Agent ◽  
Fungal Infections ◽  
Multidrug Resistant ◽  
Candida Auris ◽  
Conformationally Restricted ◽  
Normal Human

To minimize the intrinsic toxicity of the antibacterial agent hydrazinyloxadiazole 1, the hydrazine moiety was replaced with ethylenediamine (compound 7). This replacement generated a potent antifungal agent with no antibacterial activity. Notably, use of a 1,2-diaminocyclohexane moiety, as a conformationally-restricted isostere for ethylenediamine, potentiated the antifungal activity in both the cis and trans forms of N-(5-(2-([1,1’-biphenyl]-4-yl)-4-methylthiazol-5-yl)-1,3,4-oxadiazol-2-yl)cyclohexane-1,2-diamine (compounds 16 and 17). Both compounds 16 and 17 were void of any antibacterial activity; nonetheless, they showed equipotent antifungal activity in vitro to that of the most potent approved antifungal agent, amphotericin B. The promising antifungal effects of compounds 16 and 17 were maintained when assessed against an additional panel of 26 yeast and mold clinical isolates, including the Candida auris and C. krusei. Furthermore, compound 17 showed superior activity to amphotericin B in vitro against Candida glabrata and Cryptococcus gattii. Additionally, neither compound inhibited the normal human microbiota, and both possessed excellent safety profiles and were 16 times more tolerable than amphotericin B.

Linolenic acid-modified MPEG-PEI micelles for encapsulation of amphotericin B

2019 ◽  
Vol 11 (20) ◽  
pp. 2647-2662 ◽  
Author(s):  
Hongmei Xu ◽  
Fangfang Teng ◽  
Feilong Zhou ◽  
Li Zhu ◽  
Yi Wen ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Antifungal Activity ◽  
Amphotericin B ◽  
Linolenic Acid ◽  
Water Solubility ◽  
Fungal Infections ◽  
Biofilm Inhibition ◽  
Comparable Activity ◽  
Reduced Toxicity

Aim: To encapsulate amphotericin B (AmB) with reduced toxicity and comparable activity. Results & methodology: The α-linolenic acid (ALA)-modified monomethoxy polyethylene glycol-g-PEI-g-ALA conjugate was employed to prepare AmB-loaded micelles (AmB-M). In vitro activity and release behavior of AmB-M were investigated. AmB-M enhanced AmB's water-solubility to 1.2 mg/ml, showing good storage stability. AmB-M could achieve a sustained and slow release of AmB, low hemolysis activity and negligible kidney toxicity when compared with commercial AmB injection. Antifungal activity and biofilm inhibition experiments confirmed that the antifungal activity of AmB-M against Candida albicans was similar to that of AmB injection. Conclusion: Monomethoxy polyethylene glycol-g-PEI-g-ALA micelles could be a preferable choice to treat systemic fungal infections as an efficient drug delivery system.

scholarly journals In Vitro Activity of Novel Antifungal Olorofim against Filamentous Fungi and Comparison to Eight Other Antifungal Agents

2021 ◽  
Vol 7 (5) ◽  
pp. 378
Author(s):  
Ourania Georgacopoulos ◽  
Natalie S. Nunnally ◽  
Eric M. Ransom ◽  
Derek Law ◽  
Mike Birch ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Fusarium Species ◽  
Geometric Mean ◽  
Treatment Options ◽  
Antifungal Susceptibility ◽  
Dihydroorotate Dehydrogenase ◽  
Drug Classes

Olorofim is a novel antifungal drug that belongs to the orotomide drug class which inhibits fungal dihydroorotate dehydrogenase (DHODH), thus halting pyrimidine biosynthesis and ultimately DNA synthesis, cell growth and division. It is being developed at a time when many invasive fungal infections exhibit antifungal resistance or have limited treatment options. The goal of this study was to evaluate the in vitro effectiveness of olorofim against a large collection of recently isolated, clinically relevant American mold isolates. In vitro antifungal activity was determined for 246 azole-susceptible Aspergillus fumigatus isolates, five A. fumigatus with TR34/L98H-mediated resistance, 19 Rhizopus species isolates, 21 Fusarium species isolates, and one isolate each of six other species of molds. Olorofim minimum inhibitory concentrations (MICs) were compared to antifungal susceptibility testing profiles for amphotericin B, anidulafungin, caspofungin, isavuconazole, itraconazole, micafungin, posaconazole, and voriconazole. Olorofim MICs were significantly lower than those of the echinocandin and azole drug classes and amphotericin B. A. fumigatus wild type and resistant isolates shared the same MIC50 = 0.008 μg/mL. In non-Aspergillus susceptible isolates (MIC ≤ 2 μg/mL), the geometric mean (GM) MIC to olorofim was 0.54 μg/mL with a range of 0.015–2 μg/mL. Olorofim had no antifungal activity (MIC ≥ 2 μg/mL) against 10% of the collection (31 in 297), including some isolates from Rhizopus spp. and Fusarium spp. Olorofim showed promising activity against A. fumigatus and other molds regardless of acquired azole resistance.

scholarly journals ANTIFUNGAL ACTIVITY OF THE ASSOCIATION OF CARVACROL WITH AMPHOTERICIN B OR WITH KETOCONAZOLE

2019 ◽  
Vol 16 (31) ◽  
pp. 12-17
Author(s):  
Gustavo Lima SOARES ◽  
Brenda Lavínia Calixto dos SANTOS ◽  
Brenna Ravena Araújo LUZ ◽  
Wylly Araújo de OLIVEIRA
Keyword(s):  
Antifungal Activity ◽  
Amphotericin B ◽  
Inhibitory Concentration ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Aspergillus Species ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Antifungal Action

Aspergillus species are a cause of a high number of fungal infections of difficult treatment, presenting an expressive number of deaths due to the complications in the severe cases of infection. The objective was to evaluate the antifungal action of carvacrol against Aspergillus species, as well as to evaluate the interactions when associated with amphotericin B or ketoconazole. The antifungal activity of carvacrol was evaluated by the broth microdilution method. The combinations of the substances were performed by the checkerboard methodology, to determine the Index of Fractional Inhibitory Concentration. Carvacrol showed antifungal activity against all Aspergillus strains used in the trials. In combinations of substances, only a combination of carvacrol and amphotericin B presented satisfactory results. Combinations of carvacrol and ketoconazole have not shown good. It is concluded that carvacrol is a good candidate for the antifungal drug because of its good activity against Aspergillus demonstrated in the present study, as well as in other studies in the literature. Their combination in vitro with amphotericin B or ketoconazole did not present any advantages over the use of antifungal drugs alone.

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