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

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

doi:10.3389/fchem.2021.774555

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.

Highlights

Tuberculosis (TB) is an infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb), which is the leading cause of death from a single infectious agent
With the aim of synthesizing new derivatives, several modifications in ilamycin F were introduced by acylation and esterification (Scheme 1)
The result indicated that threonine methyl ester modified in C-33 carboxyl group of ilamycin F was favorable for the cytotoxic activity

Summary

INTRODUCTION

Tuberculosis (TB) is an infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb), which is the leading cause of death from a single infectious agent. Previous studies identified the target of rufomycins, caseinolytic protein C1 (ClpC1), which was different from that of the current therapeutic drugs (Sassetti et al, 2003; Lee et al, 2016; Choules et al, 2018; Choules et al, 2019; Wolf et al, 2019) Compounds of this family are a promising drug-lead for the treatment of MRD- and XRD-TB. As the main metabolite of the mutant strain S. atratus SCSIO ZH16 ΔilaR, the yield of ilamycin F is about 400–500 mg/L in its mutant In this regard, ilamycin F is ideally utilized as a starting material for preparing new ilamycin derivatives, which will facilitate to further investigate their SAR and discover more efficient anti-TB drug leads. Several semi-synthesized derivatives display potent anti-TB activity against M. tuberculosis H37Rv with fast-onset effect and low cytotoxicity

RESULTS AND DISCUSSION

CONCLUSION

DATA AVAILABILITY STATEMENT