{"title":"从放线菌培养库中的次级代谢物中发现抗疟疾药物。","authors":"Awet Alem Teklemichael, Aiko Teshima, Asahi Hirata, Momoko Akimoto, Mayumi Taniguchi, Gholam Khodakaramian, Takashi Fujimura, Fuyuki Tokumasu, Kenji Arakawa, Shusaku Mizukami","doi":"10.1186/s41182-024-00608-1","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Natural products play a key role as potential sources of biologically active substances for the discovery of new drugs. This study aimed to identify secondary metabolites from actinomycete library extracts that are potent against the asexual stages of Plasmodium falciparum (P. falciparum).</p><p><strong>Methods: </strong>Secondary metabolites from actinomycete library extracts were isolated from culture supernatants by ethyl acetate extraction. Comprehensive screening was performed to identify novel antimalarial compounds from the actinomycete library extracts (n = 28). The antimalarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) lines of P. falciparum. The cytotoxicity was then evaluated in primary adult mouse brain (AMB) cells.</p><p><strong>Results: </strong>Out of the 28 actinomycete extracts, 17 showed parasite growth inhibition > 50% at a concentration of 50 µg/mL, nine were identified with an IC<sub>50</sub> value < 10 µg/mL, and seven suppressed the parasite significantly with an IC<sub>50</sub> value < 5 µg/mL. The extracts from Streptomyces aureus strains HUT6003 (Extract ID number: 2), S. antibioticus HUT6035 (8), and Streptomyces sp. strains GK3 (26) and GK7 (27), were found to have the most potent antimalarial activity with IC<sub>50</sub> values of 0.39, 0.09, 0.97, and 0.36 µg/mL (against 3D7), and 0.26, 0.22, 0.72, and 0.21 µg/mL (against Dd2), respectively. Among them, Streptomyces antibioticus strain HUT6035 (8) showed the highest antimalarial activity with an IC<sub>50</sub> value of 0.09 µg/mL against 3D7 and 0.22 µg/mL against Dd2, and a selective index (SI) of 188 and 73.7, respectively.</p><p><strong>Conclusion: </strong>Secondary metabolites obtained from the actinomycete extracts showed promising antimalarial activity in vitro against 3D7 and Dd2 cell lines of P. falciparum with minimal toxicity. Therefore, secondary metabolites obtained from actinomycete extracts represent an excellent starting point for the development of antimalarial drug leads.</p>","PeriodicalId":23311,"journal":{"name":"Tropical Medicine and Health","volume":"52 1","pages":"47"},"PeriodicalIF":3.6000,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11232162/pdf/","citationCount":"0","resultStr":"{\"title\":\"Discovery of antimalarial drugs from secondary metabolites in actinomycetes culture library.\",\"authors\":\"Awet Alem Teklemichael, Aiko Teshima, Asahi Hirata, Momoko Akimoto, Mayumi Taniguchi, Gholam Khodakaramian, Takashi Fujimura, Fuyuki Tokumasu, Kenji Arakawa, Shusaku Mizukami\",\"doi\":\"10.1186/s41182-024-00608-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Natural products play a key role as potential sources of biologically active substances for the discovery of new drugs. This study aimed to identify secondary metabolites from actinomycete library extracts that are potent against the asexual stages of Plasmodium falciparum (P. falciparum).</p><p><strong>Methods: </strong>Secondary metabolites from actinomycete library extracts were isolated from culture supernatants by ethyl acetate extraction. Comprehensive screening was performed to identify novel antimalarial compounds from the actinomycete library extracts (n = 28). The antimalarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) lines of P. falciparum. The cytotoxicity was then evaluated in primary adult mouse brain (AMB) cells.</p><p><strong>Results: </strong>Out of the 28 actinomycete extracts, 17 showed parasite growth inhibition > 50% at a concentration of 50 µg/mL, nine were identified with an IC<sub>50</sub> value < 10 µg/mL, and seven suppressed the parasite significantly with an IC<sub>50</sub> value < 5 µg/mL. The extracts from Streptomyces aureus strains HUT6003 (Extract ID number: 2), S. antibioticus HUT6035 (8), and Streptomyces sp. strains GK3 (26) and GK7 (27), were found to have the most potent antimalarial activity with IC<sub>50</sub> values of 0.39, 0.09, 0.97, and 0.36 µg/mL (against 3D7), and 0.26, 0.22, 0.72, and 0.21 µg/mL (against Dd2), respectively. Among them, Streptomyces antibioticus strain HUT6035 (8) showed the highest antimalarial activity with an IC<sub>50</sub> value of 0.09 µg/mL against 3D7 and 0.22 µg/mL against Dd2, and a selective index (SI) of 188 and 73.7, respectively.</p><p><strong>Conclusion: </strong>Secondary metabolites obtained from the actinomycete extracts showed promising antimalarial activity in vitro against 3D7 and Dd2 cell lines of P. falciparum with minimal toxicity. Therefore, secondary metabolites obtained from actinomycete extracts represent an excellent starting point for the development of antimalarial drug leads.</p>\",\"PeriodicalId\":23311,\"journal\":{\"name\":\"Tropical Medicine and Health\",\"volume\":\"52 1\",\"pages\":\"47\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2024-07-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11232162/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Tropical Medicine and Health\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1186/s41182-024-00608-1\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"TROPICAL MEDICINE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Tropical Medicine and Health","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1186/s41182-024-00608-1","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"TROPICAL MEDICINE","Score":null,"Total":0}
Discovery of antimalarial drugs from secondary metabolites in actinomycetes culture library.
Background: Natural products play a key role as potential sources of biologically active substances for the discovery of new drugs. This study aimed to identify secondary metabolites from actinomycete library extracts that are potent against the asexual stages of Plasmodium falciparum (P. falciparum).
Methods: Secondary metabolites from actinomycete library extracts were isolated from culture supernatants by ethyl acetate extraction. Comprehensive screening was performed to identify novel antimalarial compounds from the actinomycete library extracts (n = 28). The antimalarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) lines of P. falciparum. The cytotoxicity was then evaluated in primary adult mouse brain (AMB) cells.
Results: Out of the 28 actinomycete extracts, 17 showed parasite growth inhibition > 50% at a concentration of 50 µg/mL, nine were identified with an IC50 value < 10 µg/mL, and seven suppressed the parasite significantly with an IC50 value < 5 µg/mL. The extracts from Streptomyces aureus strains HUT6003 (Extract ID number: 2), S. antibioticus HUT6035 (8), and Streptomyces sp. strains GK3 (26) and GK7 (27), were found to have the most potent antimalarial activity with IC50 values of 0.39, 0.09, 0.97, and 0.36 µg/mL (against 3D7), and 0.26, 0.22, 0.72, and 0.21 µg/mL (against Dd2), respectively. Among them, Streptomyces antibioticus strain HUT6035 (8) showed the highest antimalarial activity with an IC50 value of 0.09 µg/mL against 3D7 and 0.22 µg/mL against Dd2, and a selective index (SI) of 188 and 73.7, respectively.
Conclusion: Secondary metabolites obtained from the actinomycete extracts showed promising antimalarial activity in vitro against 3D7 and Dd2 cell lines of P. falciparum with minimal toxicity. Therefore, secondary metabolites obtained from actinomycete extracts represent an excellent starting point for the development of antimalarial drug leads.
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