Semisynthetic Amides of Polyene Antibiotic Natamycin.

Autor: Tevyashova AN; Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow119021, Russia., Efimova SS; Institute of Cytology of the Russian Academy of Sciences, 4 Tikhoretsky Avenue, St. Petersburg194064, Russia., Alexandrov AI; Federal Research Center 'Fundamentals of Biotechnology' of the Russian Academy of Sciences, Bach Institute of Biochemistry, 33 Leninsky Avenue, Bld. 2, Moscow119071, Russia., Ghazy ESMO; Federal Research Center 'Fundamentals of Biotechnology' of the Russian Academy of Sciences, Bach Institute of Biochemistry, 33 Leninsky Avenue, Bld. 2, Moscow119071, Russia.; Institute of Biochemical Technology and Nanotechnology, Peoples' Friendship University of Russia (RUDN), 6 Miklukho-Maklaya Street, Moscow117198, Russia.; Department of Microbiology, Faculty of Pharmacy, Tanta University, Tanta31111, Egypt., Bychkova EN; Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow119021, Russia., Solovieva SE; Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow119021, Russia., Zatonsky GB; Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow119021, Russia., Grammatikova NE; Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow119021, Russia., Dezhenkova LG; Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow119021, Russia., Pereverzeva ER; Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow119021, Russia., Isakova EB; Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow119021, Russia., Ostroumova OS; Institute of Cytology of the Russian Academy of Sciences, 4 Tikhoretsky Avenue, St. Petersburg194064, Russia., Omelchuk OA; Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow119021, Russia., Muravieva VV; National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparin Street, Moscow117997, Russia., Krotova MM; National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparin Street, Moscow117997, Russia., Priputnevich TV; National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparin Street, Moscow117997, Russia., Shchekotikhin AE; Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow119021, Russia.
Jazyk: angličtina
Zdroj: ACS infectious diseases [ACS Infect Dis] 2023 Jan 13; Vol. 9 (1), pp. 42-55. Date of Electronic Publication: 2022 Dec 23.
DOI: 10.1021/acsinfecdis.2c00237
Abstrakt: Natamycin is a macrolide polyene antibiotic, characterized by a potent broad spectrum antifungal activity and low toxicity. However, it is not used for the treatment of systemic mycoses due to its low bioavailability and low solubility in aqueous solutions. In order to create new semisynthetic antifungal agents for treatment of mycoses, a series of water-soluble amides of natamycin were synthesized. Antifungal activities of natamycin derivatives were investigated against Candida spp. , including a panel of Candida auris clinical isolates and filamentous fungi. Toxicity for mammalian cells was assayed by monitoring antiproliferative activity against human postnatal fibroblasts (HPF) and human embryonic kidney cells (HEK293). By comparing leakage of contents from ergosterol versus cholesterol containing vesicles, a ratio that characterizes the efficacy and safety of natamycin and its derivatives was determined (EI, efficiency index). Ability of all tested semisynthetic natamycines to prevent proliferation of the yeast Candida spp. cells was comparable or even slightly higher to those of parent antibiotic. Interestingly, amide 8 was more potent than natamycin ( 1 ) against all tested C. auris strains (MIC values 2 μg/mL vs 8 μg/mL, respectively). Among 7 derivatives, amide 10 with long lipophilic side chains showed the highest EI and strong antifungal activity in vitro but was more toxic against HPF. In vivo experiments with amide 8 showed in vivo efficacy on a mouse candidemia model with a larger LD 50 /ED 50 ratio in comparison to amphotericin B.
Databáze: MEDLINE
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