Semi-Synthesis of Marine-Derived Ilamycin F Derivatives and Their Antitubercular Activities

Jun Li; Zhiyong Liu; Mingye Hong; Changli Sun; Tianyu Zhang; Hua Zhang; Jianhua Ju; Junying Ma

doi:10.3389/fchem.2021.774555

Semi-Synthesis of Marine-Derived Ilamycin F Derivatives and Their Antitubercular Activities

Front Chem. 2021 Oct 29:9:774555. doi: 10.3389/fchem.2021.774555. eCollection 2021.

Authors

Jun Li^{1

2}, Zhiyong Liu³, Mingye Hong⁴, Changli Sun^{1

2}, Tianyu Zhang³, Hua Zhang⁴, Jianhua Ju^{1

2

5}, Junying Ma^{1

2

5}

Affiliations

¹ CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.
² Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China.
³ Tuberculosis Research Laboratory, State Key Laboratory of Respiratory Disease, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
⁴ Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Laboratory Medicine, Guangdong Medical University, Dongguan, China.
⁵ College of Oceanology, University of Chinese Academy of Sciences, Qingdao, China.

Abstract

Tuberculosis (TB) is still a global disease threatening people's lives. With the emergence of multi-drug-resistant Mycobacterium tuberculosis the prevention and control of tuberculosis faces new challenges, and the burden of tuberculosis treatment is increasing among the world. Ilamycins are novel cyclopeptides with potent anti-TB activities, which have a unique target protein against M. tuberculosis and drug-resistant strains. Herein, ilamycin F, a major secondary metabolite isolated from the marine-derived mutant strain Streptomyces atratus SCSIO ZH16 ΔilaR, is used as a scaffold to semi-synthesize eighteen new ilamycin derivatives (ilamycin NJL1-NJL18, 1-18). Our study reveals that four of ilamycin NJLs (1, 6, 8, and 10) have slightly stronger anti-TB activities against Mtb H37Rv (minimum inhibitory concentration, 1.6-1.7 μM) compared with that of ilamycin F on day 14th, but obviously display more potent activities than ilamycin F on day 3rd, indicating anti-TB activities of these derivatives with fast-onset effect. In addition, cytotoxic assays show most ilamycin NJLs with low cytotoxicity except ilamycin NJL1 (1). These findings will promote the further exploration of structure-activity relationships for ilamycins and the development of anti-TB drugs.

Keywords: antitubercular activity; cyclopeptide; derivatization; ilamycin; semi-synthesis; streptomycetes.