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

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.

Marine natural products

“…Review highlights included those describing advances in phenazine chemistry over the past decade, 81 a catalogue of 1062 terpenoid NPs produced by bacteria, entitled "Bacterial terpenome", 82 overviews of the biology and chemistry of macrolactins 83 and thiopeptides, 84 how the recording and mining of MS data is transforming NP research, 85 N-N bond formation reactions involved in NP biosynthesis, 86 developing techniques that can be applied to single cells for accelerating microbial NP research, 87 recent highlights of biosynthetic studies on marine bacteria products, 88 a summary detailing 127 halogenated compounds identied from marine actinomycetes (1992-2022), 89 use of synthetic biology to elucidate NP BGCs encoded in Streptomyces genomes, 90 chemical labelling strategies for NP detection and isolation, 91 cryptic halogenation reactions associated with NP biosynthesis, 92 volatile nitrogenous compounds from bacteria, 93 the versatile role of condensation domains in NP biosynthesis, 94 importance of microbial NP databases and their impact in the multi-omics era, 95 diversity, mechanism and selectivity of polyketide b-branching, 96 and an overview of natural antiplasmodial lead compounds (648 NPs from various natural sources; 2013-2019). 97 Other marine bacterial research that made noteworthy contributions to the eld included the enhanced production (3.8-fold increase) of the cytotoxic and antibacterial compound ohmyungsamycin A that was achieved via adenylation domain engineering and optimisation of culture conditions, 98 the semisynthesis of 18 ilamycin F derivatives, several of which had improved anti-tubercular activity compared to the MNP, 99 research on the biosynthesis of anthraquinone-fused enediynes (e.g. dynemicin A) that has delivered insights into the biosynthetic enzymes and pathways associated with this rare chemotype, 100 and identication of a C-glycosyltransferase involved in the biosynthesis of the pyranonaphthoquinone medermycin.…”

“…Other marine bacterial research that made noteworthy contributions to the field included the enhanced production (3.8-fold increase) of the cytotoxic and antibacterial compound ohmyungsamycin A that was achieved via adenylation domain engineering and optimisation of culture conditions, 98 the semi-synthesis of 18 ilamycin F derivatives, several of which had improved anti-tubercular activity compared to the MNP, 99 research on the biosynthesis of anthraquinone-fused enediynes ( e.g. dynemicin A) that has delivered insights into the biosynthetic enzymes and pathways associated with this rare chemotype, 100 and identification of a C -glycosyltransferase involved in the biosynthesis of the pyranonaphthoquinone medermycin.…”

Total Synthesis and Biological Evaluation of Modified Ilamycin Derivatives

“…Very recently, a wide range of new ilamycins/rufomycins were described, differing mainly in their combination of different amino acid oxidation levels and the N -prenyl substituent of the tryptophan subunit (alkene, epoxide, diol) [ 22 ]. In addition, a total of 18 new Ilamycin F (Ila F) derivatives were obtained by semi-synthesis from Ila F through modification of the nitrotyrosine as well as δ-hydroxyleucine unit [ 23 ]. Ilamycin E (Ila E) has been found to be one of the most active examples so far (MIC: ~10 nM) ( Figure 1 ), being more active than the rifampicin used as a positive control [ 22 , 23 , 24 , 25 ].…”

“…In addition, a total of 18 new Ilamycin F (Ila F) derivatives were obtained by semi-synthesis from Ila F through modification of the nitrotyrosine as well as δ-hydroxyleucine unit [ 23 ]. Ilamycin E (Ila E) has been found to be one of the most active examples so far (MIC: ~10 nM) ( Figure 1 ), being more active than the rifampicin used as a positive control [ 22 , 23 , 24 , 25 ]. Structure–activity relationship (SAR) studies of the isolated derivatives indicated that cyclized compounds such as Ila E are more active than open-chain leucine derivatives.…”

“…Structure–activity relationship (SAR) studies of the isolated derivatives indicated that cyclized compounds such as Ila E are more active than open-chain leucine derivatives. Oxidation of the prenyl side chain did not obviously affect activity, but the nitro group on the tyrosine seems to play an important role [ 22 , 23 , 24 ].…”