Recent advances in antifungal drug discovery based on polyene macrolide antibiotics

Omelchuk, Olga A.; Tevyashova, Anna N.; Shchekotikhin, Andrey E.

doi:10.1070/rcr4841

Cited by 24 publications

(10 citation statements)

References 66 publications

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“…There are several antifungal compounds in clinical use, 7 but invasive fungal infections can only be treated with four classes of antifungal agents: polyenes, flucytosine, azoles and echinocandins 8 . Amphotericin B (AmB) stands out among the polyenes.…”

Section: Introductionmentioning

confidence: 99%

Preclinical safety evaluation of amphotericin A21: A novel antifungal

Ortega‐Blake

Fernández‐Zertuche

Regla

et al. 2021

Basic Clin Pharma Tox

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Safety studies are essential in drug development. This study evaluates the safety of Amphotericin A21 (AmB‐A21), a derivative of amphotericin B with antifungal therapeutic potential. We performed a chronic toxicity study, a targeted organ study and a dermal irritation test. To evaluate chronic toxicity, 18 male adult rats were treated orally with AmB‐21 (2 mg/kg) for 26 weeks. The effects on body‐weight and animal health were measured, and haematological, clinical chemistry and histopathological tests were conducted on various organs. In the target organ toxicity study, male adult rats received a daily oral dose of AmB‐21 (2 mg/kg) for 6 and 17 weeks; testicle histology and testosterone levels were then evaluated. For the dermal irritation study, AmB‐21 (200 and 1000 mg/kg) was placed on the skin of adult male rabbits; macroscopic and microscopic studies, as well as haematological and clinical chemistry tests were then conducted. The chronic toxicity study revealed that AmB‐21 caused testicle damage, and the testicle‐targeted study showed structural alterations and changes in testosterone levels at 17 weeks. However, these alterations were no longer observed 8 weeks after discontinuation of treatment, and the testes showed very similar characteristics to those in the control group. The dermal irritation study showed skin thickening and reddening in rabbits treated with 2000 mg of AmB‐A21 after 14 days of exposure. This same group also showed changes in liver enzymes, renal parameters and platelet levels. Based on our results, we consider AmB‐21 to be a potential candidate for safe, long‐term antifungal treatment given its reduced side effects.

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Section: Introductionmentioning

confidence: 99%

Preclinical safety evaluation of amphotericin A21: A novel antifungal

Ortega‐Blake

Fernández‐Zertuche

Regla

et al. 2021

Basic Clin Pharma Tox

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“…Nevertheless, the application of AmB is limited by its low solubility in aqueous media and by serious side-effects such as infusion-related reactions, hemolytic toxicity, and nephrotoxicity . Therefore, it is imperative to search for new polyene derivatives with better chemotherapeutic properties …”

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confidence: 99%

“…3 Therefore, it is imperative to search for new polyene derivatives with better chemotherapeutic properties. 4 The mechanism of action of antifungal polyenes has been studied for a long time but still remains controversial. The first described mode of action was pore formation after binding to sterols that are present in the cell membrane.…”

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confidence: 99%

Discovery of Amphamide, a Drug Candidate for the Second Generation of Polyene Antibiotics

et al. 2020

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Amphotericin B (AmB, 1) is the drug of choice for treating the most serious systemic fungal or protozoan infections. Nevertheless, its application is limited by low solubility in aqueous media and serious side effects such as infusion-related reactions, hemolytic toxicity, and nephrotoxicity. Owing to these limitations, it is essential to search for the polyene derivatives with better chemotherapeutic properties. With the objective of obtaining AmB derivatives with lower self-aggregation and improved solubility, we synthesized a series of amides of AmB bearing an additional basic group in the introduced residue. The screening of antifungal activity in vitro revealed that N-(2-aminoethyl)amide of AmB (amphamide, 6) had superior antifungal activity compared to that of the paternal AmB. Preclinical studies in mice confirmed that compound 6 had a much lower acute toxicity and higher antifungal efficacy in the model of mice candidosis sepsis compared with that of AmB (1). Thus, the discovered amphamide is a promising drug candidate for the second generation of polyene antibiotics and is also prospective for in-depth preclinical and clinical evaluation.

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“…Research at G. F. Gause Institute of New Antibiotics (GINA) aimed at the design of new antifungal agents [1] explored chemical modification of AmB [2 -5]. The synthesized semisynthetic AmB derivatives included the N-(2-aminoethyl)amide of AmB (amphamide) (Fig.…”

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confidence: 99%

Preclinical Pharmacokinetics Study of Amphamide: a New Semisynthetic Antifungal Antibiotic

et al. 2020

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The pharmacokinetics of amphamide, a new semisynthetic antifungal antibiotic, are studied after intravenous injection to rats and rabbits. The amphamide concentration in biological samples was determined by HPLC. Amphamide pharmacokinetics in rabbits were nonlinear. Amphamide levels in animal blood plasma decreased in a triphasic manner. The total clearance and steady-state distribution volume were greater in rats than in rabbits (0.85 vs. 0.3 -0.5 mL × min -1 × kg -1 and 1.5 vs. 0.6 -0.9 L/kg, respectively). The mean residence times of amphamide in rats and rabbits were similar (30 vs. 27 -43 h, respectively). The elimination half-lives calculated using a three-compartment model were 24 h for rats and 31 h for rabbits. The availability of rat tissue for amphamide ranged from 100% (brain) to 1700% (kidneys).

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Recent advances in antifungal drug discovery based on polyene macrolide antibiotics

Cited by 24 publications

References 66 publications

Preclinical safety evaluation of amphotericin A21: A novel antifungal

Preclinical safety evaluation of amphotericin A21: A novel antifungal

Discovery of Amphamide, a Drug Candidate for the Second Generation of Polyene Antibiotics

Preclinical Pharmacokinetics Study of Amphamide: a New Semisynthetic Antifungal Antibiotic

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