Total Synthesis of Three Families of Natural Antibiotics: Anthrabenzoxocinones, Fasamycins/Naphthacemycins, and Benastatins

Jiang, Delu; Xin, Kunyun; Yang, Baochao; Chen, Yanyu; Zhang, Quan; He, Haibing; Gao, Shuanhu

doi:10.31635/ccschem.020.202000151

Cited by 56 publications

(13 citation statements)

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“…It has been shown that fasamycin A inhibits type II fatty acid synthases (FASII) essential for bacterial cell viability and displays a potent inhibitory effect against FASII in vitro with low IC 50 value (50 µg/mL) [5]. Due to their potent antibacterial activities, fasamycins have attracted attention to medicinal chemists to perform total synthesis and study the structure-activity relationship of the fasamycin scaffold [8][9][10]. During our natural product screening program, we found that the soil isolate, Streptomyces sp.…”

Section: Introductionmentioning

confidence: 99%

Discovery of New Antibacterial Accramycins from a Genetic Variant of the Soil Bacterium, Streptomyces sp. MA37

et al. 2020

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Continued mining of natural products from the strain Streptomyces sp. MA37 in our laboratory led to the discovery of a minor specialized metabolite (SM) called accramycin A. Owing to its low yield (0.2 mg/L) in the wild type strain, we investigated the roles of regulatory genes in the corresponding biosynthetic gene cluster (acc BGC) through gene inactivation with the aim of improving the titer of this compound. One of the resulting mutants (∆accJ) dramatically upregulated the production of accramycin A 1 by 330-fold (66 mg/L). Furthermore, ten new metabolites, accramycins B–K 2–11, were discovered, together with two known compounds, naphthacemycin B112 and fasamycin C 13 from the mutant extract. This suggested that accJ, annotated as multiple antibiotic resistance regulator (MarR), is a negative regulator gene in the accramycin biosynthesis. Compounds 1–13 inhibited the Gram-positive pathogens (Staphylococcus aureus, Enterococcus faecalis) and clinical isolates Enterococcus faecium (K59-68 and K60-39) and Staphylococcus haemolyticus with minimal inhibitory concentration (MIC) values in the range of 1.5–12.5 µg/mL. Remarkably, compounds 1–13 displayed superior activity against K60-39 (MIC = 3.1–6.3 µg/mL) compared to ampicillin (MIC = 25 µg/mL), and offered promising potential for the development of accramycin-based antibiotics that target multidrug-resistant Enterococcus clinical isolates. Our results highlight the importance of identifying the roles of regulatory genes in natural product discovery.

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Section: Introductionmentioning

confidence: 99%

Discovery of New Antibacterial Accramycins from a Genetic Variant of the Soil Bacterium, Streptomyces sp. MA37

et al. 2020

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“…Our initial screening of reaction conditions showed this PEDA reaction to be sensitive to different titanium( iv ) species, and even to an equivalent of Ti(O i -Pr) 4 . 11 Photolysis using Ti(O i -Pr) 4 dosages >2.0 equivalents gave stable and comparable yield; therefore, we initially conducted our experiment using 3.0 equivalents of Ti(O i -Pr) 4 with 1.0 equivalent of a chiral ligand, employing the electron-rich 3,6-dimethoxy-2-methylbenzaldehyde 1 and electron-deficient 1-cyclohexenyl-ethanone 2 as model substrates. Four types of commonly used bidentate chiral ligands (Table S1 in the ESI † ) were examined and it was found that chiral TADDOL L1 gave a more promising result, generating the tricyclic product 3 in 70% yield with 67% ee ( Table 1A ).…”

Section: Resultsmentioning

confidence: 99%

“… 17,21 The ortho methoxy may serve as a key neighboring group that helps to stabilize the short-lived photoenolized hydroxy- o -quinodimethane diene. 11 Due to its strong Lewis acidity, the Ti-complex TS-1 preferentially associates with the electron-withdrawing groups in the dienophile, such as enones 2 , forming the transient TS-2 , which in turn facilitates a Diels–Alder reaction. The chiral cage-like environment accelerates and controls the diastereo- and enantioselectivity of the cycloaddition.…”

Section: Resultsmentioning

confidence: 99%

“…1B ). 11 We reasoned that the chiral Ti-complex would chelate both the diene and dienophile, temporarily converting an intermolecular PEDA reaction into an intramolecular one. We envisioned that this investigation would not only provide solutions to achieve the synthesis of these natural products containing an anthracenol core bearing vicinal quaternary centers ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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Construction of polycyclic structures with vicinal all-carbon quaternary stereocenters via an enantioselective photoenolization/Diels–Alder reaction

Hou

Yang

et al. 2021

Chem. Sci.

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“…It has been shown that fasamycin A inhibits type II fatty acid synthases (FASII), which are essential for bacterial cell viability, with a potent inhibitory effect against FASII in vitro in a low IC50 value (50 µg/mL) [5]. Due to their potent antibacterial activities, fasamycins have attracted the attention of medicinal chemists for total synthesis to study the structure-activity relationship of the fasamycin scaffold [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Discovery of new antibacterial accramycins from a genetic variant of the soil bacterium,Streptomycessp. MA37

Maglangit

Zhang

Kyeremeh

et al. 2020

Preprint

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Continued mining of natural products from the strain Streptomyces sp. MA37 in our laboratory led to the discovery of a minor specialised metabolite (SM) called accramycin A. Owing to its low yield (0.2mg/L) in the wild type strain, we investigated the roles of regulatory genes in the corresponding biosynthetic gene cluster (acc BGC) through gene inactivation with the aim of improving the titre of this compound. One of the resulting mutants (delta accJ) dramatically upregulated the production of accramycin A 1 by 330-fold (66mg/L). Furthermore, ten new metabolites, accramycins B-K 2-11, were discovered, together with two known compounds, naphthacemycin B1 12 and fasamycin C 13 from the mutant extract. This suggested that accJ, annotated as Multiple Antibiotic Resistance Regulator (MarR), is a negative regulator gene in the accramycin biosynthesis. Compounds 1-13 inhibited the Gram-positive pathogens (S. aureus, E. faecalis) and clinical isolates, E. faecium (K59-68 and K60-39), and S. haemolyticus with minimal inhibitory concentration (MIC) values in the range of 1.5-12.5microg/mL. Remarkably, compounds 1-13 displayed superior activity against K60-39 (MIC = 3.1-6.3microg/mL) than ampicillin (MIC = 25microg/mL), and offer promising potential for the development of accramycin-based antibiotics that target multidrug-resistant Enterococcus clinical isolates. Our results highlight the importance of identifying the roles of regulatory genes in natural product discovery.

show abstract

Total Synthesis of Three Families of Natural Antibiotics: Anthrabenzoxocinones, Fasamycins/Naphthacemycins, and Benastatins

Cited by 56 publications

References 51 publications

Discovery of New Antibacterial Accramycins from a Genetic Variant of the Soil Bacterium, Streptomyces sp. MA37

Discovery of New Antibacterial Accramycins from a Genetic Variant of the Soil Bacterium, Streptomyces sp. MA37

Construction of polycyclic structures with vicinal all-carbon quaternary stereocenters via an enantioselective photoenolization/Diels–Alder reaction

Discovery of new antibacterial accramycins from a genetic variant of the soil bacterium,Streptomycessp. MA37

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