Discovery of antimalarial drugs from secondary metabolites in actinomycetes culture library

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

Discovery of antimalarial drugs from secondary metabolites in actinomycetes culture library

Trop Med Health. 2024 Jul 9;52(1):47. doi: 10.1186/s41182-024-00608-1.

Authors

Awet Alem Teklemichael^#¹, Aiko Teshima^#^{2

3}, Asahi Hirata^{2

3}, Momoko Akimoto^{2

3}, Mayumi Taniguchi^{1

4}, Gholam Khodakaramian⁵, Takashi Fujimura^{2

3}, Fuyuki Tokumasu^{4

6

7}, Kenji Arakawa^{8

9}, Shusaku Mizukami^{10

11}

Affiliations

¹ Department of Immune Regulation, SHIONOGI Global Infectious Diseases Division, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Nagasaki, Japan.
² Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan.
³ Hiroshima Research Center for Healthy Aging (HiHA), Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan.
⁴ School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Nagasaki, Japan.
⁵ Department of Plant Protection, College of Agriculture, Bu-Ali Sina University, Hamedan, Iran.
⁶ Department of Cellular Architecture Studies, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Nagasaki, Japan.
⁷ Department of Laboratory Sciences, Graduate School of Health Sciences, Gunma University, Maebashi, Gunma, Japan.
⁸ Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan. karakawa@hiroshima-u.ac.jp.
⁹ Hiroshima Research Center for Healthy Aging (HiHA), Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan. karakawa@hiroshima-u.ac.jp.
¹⁰ Department of Immune Regulation, SHIONOGI Global Infectious Diseases Division, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Nagasaki, Japan. mizukami@nagasaki-u.ac.jp.
¹¹ School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Nagasaki, Japan. mizukami@nagasaki-u.ac.jp.

^# Contributed equally.

Abstract

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.

Keywords: Streptomyces; Actinomycete; Antimalarial; Malaria; Secondary metabolites.