Semisynthetic Amides of Amphotericin B and Nystatin A1: A Comparative Study of In Vitro Activity/Toxicity Ratio in Relation to Selectivity to Ergosterol Membranes

Tevyashova, Anna N.; Efimova, Svetlana S.; Alexandrov, Alexander I.; Omelchuk, Olga A.; Bychkova, E. N.; Zatonsky, George V.; Grammatikova, Natalia E.; Dezhenkova, Lyubov G.; Solovieva, S. E.; Ostroumova, Olga S.; Shchekotikhin, Andrey E.

doi:10.3390/antibiotics12010151

Cited by 16 publications

(9 citation statements)

References 61 publications

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“…The main fungal pathogens in humans are Candida species, which develop resistance to triazoles and echinocandins. However, resistance to AMPB (Polyene) is extremely rare, despite its use for more than 60 years as a monotherapy, mainly for invasive fungal infections [ 51 , 52 ]. For this reason, it is interesting to know whether amphotericin B-resistant yeast strains can be found in the environment.…”

Section: Discussionmentioning

confidence: 99%

Water Quality, Heavy Metals, and Antifungal Susceptibility to Fluconazole of Yeasts from Water Systems

Caicedo-Bejarano

Osorio-Vanegas

Castillo

et al. 2023

IJERPH

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Aquatic environments could be reservoirs of pathogenic yeasts with acquired antifungal resistance. The susceptibility to antifungal agents of yeasts present in the wastewater and natural waters of the city of Cali was evaluated. Samples were taken from two types of water: drinking water (Meléndez River, drinking water treatment plant “Puerto Mallarino” in the Cauca River) and wastewater (South Channel of the Cauca River, “Cañaveralejo-PTAR” wastewater treatment plant). Physico-chemical parameters, heavy metal concentration, and yeast levels were determined using standard procedures. Yeasts were identified using API 20 C AUX (BioMérieux) and sequence analysis of the ITS1-5.8S-ITS2 and D1/D2 regions of the large subunit of the ribosome. Susceptibility assays against fluconazole and amphotericin B using the minimum inhibitory concentration (MIC) test were determined using the microdilution method. The influence of physico-chemical parameters and heavy metals was established using principal component analysis (PCA). Yeast counts were higher at WWTP “PTAR” and lower at Melendez River, as expected. A total of 14 genera and 21 yeast species was identified, and the genus Candida was present at all locations. Susceptibility tests showed a 32.7% resistance profile to fluconazole in the order DWTP “Puerto Mallarino = WWTP “PTAR” > South Channel “Navarro”. There were significant differences (p < 0.05) in the physico-chemical parameters/concentration of heavy metals and yeast levels between the aquatic systems under study. A positive association was observed between yeast levels and total dissolved solids, nitrate levels, and Cr at the “PTAR” WWTP; conductivity, Zn, and Cu in the South Channel; and the presence of Pb in the “Puerto Mallarino” DWTP. Rhodotorula mucilaginosa, Candida albicans, and Candida sp. 1 were influenced by Cr and Cd, and Diutina catelunata was influenced by Fe (p < 0.05). The water systems explored in this study showed different yeast levels and susceptibility profiles, and, therefore, possible genetic differences among populations of the same species, and different physico-chemical and heavy metals concentrations, which were probably modulating the antifungal-resistant yeasts. All these aquatic systems discharge their content into the Cauca River. We highlight the importance to further investigate if these resistant communities continue to other locations in the second largest river of Colombia and to determine the risk posed to humans and animals.

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Section: Discussionmentioning

confidence: 99%

Water Quality, Heavy Metals, and Antifungal Susceptibility to Fluconazole of Yeasts from Water Systems

Caicedo-Bejarano

Osorio-Vanegas

Castillo

et al. 2023

IJERPH

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“…An essential aspect of the ongoing research is the study of the possibility of increasing the specificity of the toxic effects of the obtained biomimetics on fungal cells. Thus, the obtained nystatin amides demonstrated increased water solubility and reduced toxicity in relation to human kidney cells (HEK293) while maintaining the inhibition of ergosterol biosynthesis by fungal cells [80].…”

Section: Biomimetics With a Destructive Effect On Fungal Cellsmentioning

confidence: 95%

“…However, there is a traditional interest in biomimetics, which are chemically modified nystatin molecules, the proposed mechanism of action of which is binding to ergosterol in the structure of lipid bilayers of fungal membranes. In this case, extra-membrane aggregates are formed that inhibit the transport of amino acids and glucose through the plasma membrane of cells [80]. Finally, polyene biomimetics contribute to the formation of macropores in the cell membrane and lead to their destruction.…”

Section: Biomimetics With a Destructive Effect On Fungal Cellsmentioning

confidence: 99%

Various Biomimetics, Including Peptides as Antifungals

Efremenko,

Aslanli,

Stepanov

et al. 2023

Biomimetics

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Biomimetics, which are similar to natural compounds that play an important role in the metabolism, manifestation of functional activity and reproduction of various fungi, have a pronounced attraction in the current search for new effective antifungals. Actual trends in the development of this area of research indicate that unnatural amino acids can be used as such biomimetics, including those containing halogen atoms; compounds similar to nitrogenous bases embedded in the nucleic acids synthesized by fungi; peptides imitating fungal analogs; molecules similar to natural substrates of numerous fungal enzymes and quorum-sensing signaling molecules of fungi and yeast, etc. Most parts of this review are devoted to the analysis of semi-synthetic and synthetic antifungal peptides and their targets of action. This review is aimed at combining and systematizing the current scientific information accumulating in this area of research, developing various antifungals with an assessment of the effectiveness of the created biomimetics and the possibility of combining them with other antimicrobial substances to reduce cell resistance and improve antifungal effects.

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“…After the POPC/ERG (67/33 mol.%) and POPC/CHOL (67/33 mol.%) bilayers were completely stabilized in time, AmB was added from a 10 mM stock solution in DMSO to the in -compartment up to concentrations in the ranges of 0.5–8 and 3–10 µM, respectively, to obtain an integral current (more than 50 pA). The AmB concentrations were chosen according to [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…AmB belongs to the polyene macrolides with a fungicidal mechanism of action accomplished mainly through pore formation in the membranes of fungal cells by the assembly of antibiotic and ergosterol (ERG) molecules, which induces outflow of electrolytes and other substances from the intracellular medium [ 9 , 10 , 11 , 12 ]. In planar lipid bilayers, addition of AmB on one side leads to the formation of predominantly cation-selective pores [ 13 , 14 ]. Using solid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations, the three-dimensional structure of the AmB pore in the bilayers formed from palmitoyloleoylphosphocholine (POPC) and ERG has been resolved as a single-length heptamer assembly [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Triggering the Amphotericin B Pore-Forming Activity by Phytochemicals

2023

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The macrolide polyene antibiotic amphotericin B (AmB), remains a valuable drug to treat systemic mycoses due to its wide antifungal activity and low probability of developing resistance. The high toxicity of AmB, expressed in nephropathy and hemolysis, could be partially resolved by lowering therapeutic AmB concentration while maintaining efficacy. This work discusses the possibility of using plant polyphenols and alkaloids to enhance the pore-forming and consequently antifungal activity of AmB. We demonstrated that phloretin, phlorizin, naringenin, taxifolin, quercetin, biochanin A, genistein, resveratrol, and quinine led to an increase in the integral AmB-induced transmembrane current in the bilayers composed of palmitoyloleoylphosphocholine and ergosterol, while catechin, colchicine, and dihydrocapsaicin did not practically change the AmB activity. Cardamonin, 4′-hydroxychalcone, licochalcone A, butein, curcumin, and piperine inhibited AmB-induced transmembrane current. Absorbance spectroscopy revealed no changes in AmB membrane concentration with phloretin addition. A possible explanation of the potentiation is related to the phytochemical-produced changes in the elastic membrane properties and the decrease in the energy of formation of the lipid mouth of AmB pores, which is partially confirmed by differential scanning microcalorimetry. The possibility of AmB interaction with cholesterol in the mammalian cell membranes instead of ergosterol in fungal membranes, determines its high toxicity. The replacement of ergosterol with cholesterol in the membrane lipid composition led to a complete loss or a significant decrease in the potentiating effects of tested phytochemicals, indicating low potential toxicity of these compounds and high therapeutic potential of their combinations with the antibiotic. The discovered combinations of AmB with plant molecules that enhance its pore-forming ability in ergosterol-enriched membranes, seem to be promising for further drug development in terms of the toxicity decrease and efficacy improvement.

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Semisynthetic Amides of Amphotericin B and Nystatin A1: A Comparative Study of In Vitro Activity/Toxicity Ratio in Relation to Selectivity to Ergosterol Membranes

Cited by 16 publications

References 61 publications

Water Quality, Heavy Metals, and Antifungal Susceptibility to Fluconazole of Yeasts from Water Systems

Water Quality, Heavy Metals, and Antifungal Susceptibility to Fluconazole of Yeasts from Water Systems

Various Biomimetics, Including Peptides as Antifungals

Triggering the Amphotericin B Pore-Forming Activity by Phytochemicals

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