Synergistic antifungal interactions of amphotericin B with 4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol

Chudzik, Barbara; Bonio, Katarzyna; Dąbrowski, Wojciech; Pietrzak, Daniel; Niewiadomy, Andrzej; Olender, Alina; Małodobry, Katarzyna; Gagoś, Mariusz

doi:10.1038/s41598-019-49425-1

Cited by 33 publications

(35 citation statements)

References 60 publications

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“…It is therefore likely that the amine, resorcynyl para-phenolic group, and the remaining heteroatoms of the thiadiazole ring may constitute the vehicle for synergistic action with kanamycin against S. aureus. Previously, the synergistic antifungal interactions were documented to occur between 1,3,4-thiadiazoles and antifungal agent amphotericin B [12]. In this context, the results obtained in our current work confirm that the synergism with various antibiotics is yet another aspect of the biological activity of 1,3,4-thiadiazoles worth investigating.…”

Section: Antibacterial Activitysupporting

confidence: 87%

“…Numerous reports have highlighted the antimicrobial, anticancer, antioxidative, or anticonvulsant activities as characteristic of 1,3,4-thiadiazoles [6][7][8]. Due to these interesting features the thiadiazole-derived compounds were extensively studied in our group [9][10][11][12][13], with several 1,3,4-thiadiazole derivatives reported to possess significant acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition activities rendering them as potential anti-neurodegenerative agents [14].…”

Section: Introductionmentioning

confidence: 99%

“…Secondly, given the fact that the thiadiazole derivatives and especially the metal complexes obtained are novel, their antibacterial and antioxidant activity was assessed for a first time. Thirdly, based on the synergistic antifungal effects that are characteristic of the structurally similar thiadiazoles [12], a possibility for the synergism with commercial antibacterial agent, kanamycin, was examined. Our studies were driven by hypotheses that determination of the metal-binding ability of thiadiazole ligands obtained may be a new approach to treatment of neurodegenerative disorders, while the assessment of their synergistic interactions with known antibiotics may shed new light on the formulation of more effective antibacterial medicines.…”

Section: Introductionmentioning

confidence: 99%

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Structural Features of 1,3,4-Thiadiazole-Derived Ligands and Their Zn(II) and Cu(II) Complexes Which Demonstrate Synergistic Antibacterial Effects with Kanamycin

Karcz

Matwijczuk

Kamiński

et al. 2020

IJMS

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Classical synthetic protocols were applied for the isolation of three novel 1,3,4-thiadiazole derivatives which were then complexed with the biologically important Cu(II) and Zn(II) ions. All free ligands and their corresponding complexes were characterized using a number of spectroscopic techniques including Ultraviolet-visible (UV–vis), Fluorescence, Infrared (FT-IR), tandem liquid chromatography-mass (LC-MS), X-ray diffraction (XRD), and Nuclear Magnetic Resonance (NMR) spectroscopy (1H, 13C, HSQC, HMBC). The results obtained are consistent with the formation of dihydrate complexes, in which the chelation of the metal ion occurs via one of the thiadiazole nitrogen atoms and the deprotonated hydroxyl group of the neighboring resorcynyl moiety. The Zn(II) complexes utilize a 1:1 ligand–metal ratio, while in the Cu(II) complexes the ligand–metal ratio is 2:1. Although the antibacterial testing identified moderate activity of the compounds against the tested bacterial strains and additionally modest antioxidant activity, a strong synergistic antibacterial effect against Staphylococcus aureus, using concomitant treatment of thiadiazole derivatives with the commercial antibiotic kanamycin, was observed. The most active thiadiazole derivative demonstrated a minimal inhibitory concentration (MIC) of 500 μg/mL while it was 125 μg/mL in the presence of kanamycin. Moreover, in the presence of few thiadiazole derivatives the MIC value of kanamycin decreased from 0.39 μg/mL to 0.5 μg/mL. The antioxidant activity (IC50) of the most active thiadiazole derivative was determined as 0.13 mM which was nearly three-fold lower compared to that of TROLOX (0.5 mM).

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Section: Antibacterial Activitysupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural Features of 1,3,4-Thiadiazole-Derived Ligands and Their Zn(II) and Cu(II) Complexes Which Demonstrate Synergistic Antibacterial Effects with Kanamycin

Karcz

Matwijczuk

Kamiński

et al. 2020

IJMS

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“…In this respect, the promising antifungal activity of thiadiazole, thiazine, and thiohydrazide derivatives (el-Shaaer et al, 1997;Matysiak et al, 2000;Magdolen et al, 2000;Vicentini et al, 2002;Singh and Kaushik, 2008) has attracted more attention. In particular, Chudzik et al (2019) demonstrated that 4-(5-methyl-1,3,4-thiadiazole-2-yl)benzene-1,3-diol shows strong synergistic interaction with AmB that significantly reduced the antibiotic concentration required for 100% inhibition of the growth of pathogenic fungi in vitro. Moreover, synergistic interactions were noted for strains with reduced sensitivity to AmB and azole-resistant isolates.…”

Section: Introductionmentioning

confidence: 99%

1,3-Thiazine, 1,2,3,4-Dithiadiazole, and Thiohydrazide Derivatives Affect Lipid Bilayer Properties and Ion-Permeable Pores Induced by Antifungals

Zakharova

Efimova

Yuskovets

et al. 2020

Front. Cell Dev. Biol.

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Over the past decade, thiazines, thiadiazoles, and thiohydrazides have attracted increasing attention due to their sedative, antimicrobial, antiviral, antifungal, and antitumor activities. The clinical efficacy of such drugs, as well as the possibility of developing resistance to antimicrobials, will depend on addressing a number of fundamental problems, including the role of membrane lipids during their interaction with plasma membranes. The effects of the eight 1,3-thiazine-, 1,2,3,4-dithiadiazole-, and thiohydrazide-related compounds on the physical properties of model lipid membranes and the effects on reconstituted ion channels induced by the polyene macrolide antimycotic nystatin and antifungal cyclic lipopeptides syringomycin E and fengycin were observed. We found that among the tested agents, the fluorine-containing compound N-(3,5-difluorophenyl)-benzenecarbothiohydrazide (C6) was the most effective at increasing the electric barrier for anion permeation into the hydrophobic region of the membrane and reducing the conductance of anion-permeable syringomycin pores. A decrease in the membrane boundary potential with C6 adsorption also facilitated the immersion of positively charged syringomycin molecules into the lipid bilayer and increases the pore-forming ability of the lipopeptide. Using differential scanning microcalorimetry, we showed that C6 led to disordering of membrane lipids, possibly by potentiating positive curvature stress. Therefore, we used C6 as an agonist of antifungals forming the pores that are sensitive to membrane curvature stress and lipid packing, i.e., nystatin and fengycin. The dramatic increase in transmembrane current induced by syringomycin E, nystatin, and fengycin upon C6 treatment suggests its potential in combination therapy for treating invasive fungal infections.

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“…One of the first-line therapies used to fight this infection is the polyene macrolide antibiotic amphotericin B (AmB) [2,3,18,19]. Its mechanism of action is based on the binding of the hydrophobic moiety of the molecule to the ergosterol of the fungal cell membrane, which disrupts the cellular membrane and causes the cytoplasmic content to leak out leading to cell death [20,21].…”

Section: Introductionmentioning

confidence: 99%

Preparation and In Vitro Evaluation of Alginate Microparticles Containing Amphotericin B for the Treatment of Candida Infections

Alvarez-Berríos

Aponte-Reyes

Diaz-Figueroa

et al. 2020

International Journal of Biomaterials

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Invasive candidiasis (IC) remains as a major cause of morbidity and mortality in critically ill patients. Amphotericin B (AmB) is one of the most effective antifungal agents commonly used to treat this infection. However, it induces severe side effects such as nephrotoxicity, cardiac alterations, nausea, fever, and liver damage. The utilization of drug delivery systems has been explored to overcome these limitations. Several AmB lipid formulations have been developed and are currently available in the market. Although they have the ability to reduce the main side effects of free AmB, their high cost, necessity of repeated intravenous injections for successful treatment, and incidence of pulmonary toxicity have limited their use. In the last decades, alginate has gained significant interest in drug delivery applications as a cost-effective strategy to improve the safety and therapeutic effect of toxic drugs. In this work, the clinically relevant drug AmB was encapsulated into alginate microparticles using the emulsification/external gelation method. We hypothesize that this synthesis strategy may positively impact the antifungal efficacy of AmB-loaded MCPs toward Candida albicans cells while reducing the toxicity in human lung cells. To prove this hypothesis, the ability of the microplatform to disrupt the cellular membrane potential was tested and its antifungal effectiveness toward Candida albicans cells was evaluated using the cell counting and plate count methods. Moreover, the toxicity of the microplatform in human lung cells was evaluated using CellTiter 96® AQueous cell viability assay and qualitative diffusion analysis of acridine orange. Our results demonstrated that the platform developed in this work was able to induce antifungal toxicity against Candida albicans yeast cells at the same level of free AmB with minimal toxicity to lung cells, which is one of the main side effects induced by commercial drug delivery systems containing AmB. Overall, our data provides convincing evidence about the effectiveness of the alginate-based microplatform toward Candida albicans cells. In addition, this vehicle may not require several infusions for a successful treatment while reducing the pulmonary toxic effect induced by commercial lipid formulations.

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Synergistic antifungal interactions of amphotericin B with 4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol

Cited by 33 publications

References 60 publications

Structural Features of 1,3,4-Thiadiazole-Derived Ligands and Their Zn(II) and Cu(II) Complexes Which Demonstrate Synergistic Antibacterial Effects with Kanamycin

Structural Features of 1,3,4-Thiadiazole-Derived Ligands and Their Zn(II) and Cu(II) Complexes Which Demonstrate Synergistic Antibacterial Effects with Kanamycin

1,3-Thiazine, 1,2,3,4-Dithiadiazole, and Thiohydrazide Derivatives Affect Lipid Bilayer Properties and Ion-Permeable Pores Induced by Antifungals

Preparation and In Vitro Evaluation of Alginate Microparticles Containing Amphotericin B for the Treatment of Candida Infections

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