Accramycin A, A New Aromatic Polyketide, from the Soil Bacterium, Streptomyces sp. MA37

Maglangit, Fleurdeliz; Fang, Qing; Leman, Valentin; Soldatou, Sylvia; Ebel, Rainer; Kyeremeh, Kwaku; Deng, Hai

doi:10.3390/molecules24183384

Cited by 34 publications

(69 citation statements)

References 42 publications

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“…Gentamicin (Sigma) was used as the standard antibiotic. The antibacterial assay of 1 was performed as described in our previous report [26].…”

Section: Chromatography and Isolationmentioning

confidence: 99%

“…MA37. This strain is a prolific producer of natural products including legonmycins [21], neocarazostatin A [22][23][24][25], accramycin A [26], legonoxamines [27], and organofluorines [9,28]. However, genomic analysis of the MA37 strain suggested that only a small part of the biosynthetic genes encoding for specialised metabolites were expressed under laboratory culture conditions.…”

Section: Introductionmentioning

confidence: 99%

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A Co-Culturing Approach Enables Discovery and Biosynthesis of a Bioactive Indole Alkaloid Metabolite

et al. 2020

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Whole-genome sequence data of the genus Streptomyces have shown a far greater chemical diversity of metabolites than what have been discovered under typical laboratory fermentation conditions. In our previous natural product discovery efforts on Streptomyces sp. MA37, a bacterium isolated from the rhizosphere soil sample in Legon, Ghana, we discovered a handful of specialised metabolites from this talented strain. However, analysis of the draft genome of MA37 suggested that most of the encoded biosynthetic gene clusters (BGCs) remained cryptic or silent, and only a small fraction of BGCs for the production of specialised metabolites were expressed when cultured in our laboratory conditions. In order to induce the expression of the seemingly silent BGCs, we have carried out a co-culture experiment by growing the MA37 strain with the Gram-negative bacterium Pseudomonas sp. in a co-culture chamber that allows co-fermentation of two microorganisms with no direct contact but allows exchange of nutrients, metabolites, and other chemical cues. This co-culture approach led to the upregulation of several metabolites that were not previously observed in the monocultures of each strain. Moreover, the co-culture induced the expression of the cryptic indole alkaloid BGC in MA37 and led to the characterization of the known indolocarbazole alkaloid, BE-13793C 1. Neither bacterium produced compound 1 when cultured alone. The structure of 1 was elucidated by Nuclear Magnetic Resonance (NMR), mass spectrometry analyses and comparison of experimental with literature data. A putative biosynthetic pathway of 1 was proposed. Furthermore, BE-13793C 1 showed strong anti-proliferative activity against HT-29 (ATCC HTB-38) cells but no toxic effect to normal lung (ATCC CCL-171) cells. To the best of our knowledge, this is the first report for the activity of 1 against HT-29. No significant antimicrobial and anti-trypanosomal activities for 1 were observed. This research provides a solid foundation for the fact that a co-culture approach paves the way for increasing the chemical diversity of strain MA37. Further characterization of other upregulated metabolites in this strain is currently ongoing in our laboratory.

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“…Gentamicin (Sigma) was used as the standard antibiotic. The antibacterial assay of 1 was performed as described in our previous report [26].…”

Section: Chromatography and Isolationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Co-Culturing Approach Enables Discovery and Biosynthesis of a Bioactive Indole Alkaloid Metabolite

et al. 2020

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“…In our efforts to discover natural products, we have isolated a new bacterial strain, Streptomyces sp. RK44 from the underexplored areas of Kintampo waterfalls, Ghana, Africa [5,6].…”

Section: Introductionmentioning

confidence: 99%

Signalling and Bioactive Metabolites from Streptomyces sp. RK44

Fang

Maglangit

et al. 2020

Molecules

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Streptomyces remains one of the prolific sources of structural diversity, and a reservoir to mine for novel natural products. Continued screening for new Streptomyces strains in our laboratory led to the isolation of Streptomyces sp. RK44 from the underexplored areas of Kintampo waterfalls, Ghana, Africa. Preliminary screening of the metabolites from this strain resulted in the characterization of a new 2-alkyl-4-hydroxymethylfuran carboxamide (AHFA) 1 together with five known compounds, cyclo-(L-Pro-Gly) 2, cyclo-(L-Pro-L-Phe) 3, cyclo-(L-Pro-L-Val) 4, cyclo-(L-Leu-Hyp) 5, and deferoxamine E 6. AHFA 1, a methylenomycin (MMF) homolog, exhibited anti-proliferative activity (EC50 = 89.6 µM) against melanoma A2058 cell lines. This activity, albeit weak is the first report amongst MMFs. Furthermore, the putative biosynthetic gene cluster (ahfa) was identified for the biosynthesis of AHFA 1. DFO-E 6 displayed potent anti-plasmodial activity (IC50 = 1.08 µM) against P. falciparum 3D7. High-resolution electrospray ionization mass spectrometry (HR ESIMS) and molecular network assisted the targeted-isolation process, and tentatively identified six AHFA analogues, 7–12 and six siderophores 13–18.

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“…MA37 is a highly prolific producer of SMs with great chemical diversity, including pyrrolizidine alkaloids [11], carbazoles [12][13][14][15][16], siderophores [17,18], and fluorinated compounds [19][20][21][22][23][24]. More recently, we discovered a new naphthacemycin congener, accramycin A 1, as one of the minor SMs in the MA37 wild type (WT) strain (0.2 mg/L) [25]. Two mono-chlorinated accramycin derivatives were also tentatively assigned via molecular network analysis.…”

Section: Introductionmentioning

confidence: 99%

“…Based on the previous knowledge of fasamycins and formicamycins [4], the putative biosynthetic gene cluster (acc BGC) of 1 was identified [25]. The biosynthetic enzymes encoded in the acc BGC displays high amino acid (AA) similarity with the ones in fasamycins and formicamycins, including the FADdependent halogenation enzyme (AccV) which shares high AA identity to the chlorinase, ForV encoded in the fasamycin and formicamycin BGCs from Streptomyces formicae [4].…”

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.

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Accramycin A, A New Aromatic Polyketide, from the Soil Bacterium, Streptomyces sp. MA37

Cited by 34 publications

References 42 publications

A Co-Culturing Approach Enables Discovery and Biosynthesis of a Bioactive Indole Alkaloid Metabolite

A Co-Culturing Approach Enables Discovery and Biosynthesis of a Bioactive Indole Alkaloid Metabolite

Signalling and Bioactive Metabolites from Streptomyces sp. RK44

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

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