Momomycin, an Antiproliferative Cryptic Metabolite from the Oxytetracycline Producer <i>Streptomyces rimosus</i>

Li, Yuchen; Lee, Seoung Rak; Han, Esther J.; Seyedsayamdost, Mohammad R.

doi:10.1002/anie.202208573

Cited by 13 publications

(14 citation statements)

References 63 publications

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“…We also unexpectedly found the biotransformation of the anticancer drug FDP ( 2 ) to F-Ade ( 6 ), which showed significant antibacterial activity, while the original drug did not. This result indicates a broader application of the HiTES method to find biotransformed products as well as cryptic metabolites from microorganisms. − ,− …”

Section: Discussionmentioning

confidence: 86%

Characterization of Chemical Interactions between Clinical Drugs and the Oral Bacterium, Corynebacterium matruchotii, via Bioactivity-HiTES

Lee,

Kim,

Lee

et al. 2024

ACS Chem. Biol.

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In the field of natural product research, the rediscovery of already-known compounds is one of the significant issues hindering new drug development. Recently, an innovative approach called bioactivity-HiTES has been developed to overcome this limitation, and several new bioactive metabolites have been successfully characterized by this method. In this study, we applied bioactivity-HiTES to Corynebacterium matruchotii, the human oral bacterium, with 3120 clinical drugs as potential elicitors. As a result, we identified two cryptic metabolites, methylindole-3-acetate (MIAA) and indole-3-acetic acid (IAA), elicited by imidafenacin, a urinary antispasmodic drug approved by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). MIAA showed weak antibacterial activity against a pulmonary disease-causing Mycobacterium conceptionense with an IC 50 value of 185.7 μM. Unexpectedly, we also found that C. matruchotii metabolized fludarabine phosphate, a USFDA-approved anticancer drug, to 2fluoroadenine which displayed moderate antibacterial activity against both Bacillus subtilis and Escherichia coli, with IC 50 values of 8.9 and 20.1 μM, respectively. Finally, acelarin, a prodrug of the anticancer drug gemcitabine, was found to exhibit unreported antibacterial activity against B. subtilis with an IC 50 value of 33.6 μM through the bioactivity-HiTES method as well. These results indicate that bioactivity-HiTES can also be applied to discover biotransformed products in addition to finding cryptic metabolites in microbes.

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Section: Discussionmentioning

confidence: 86%

Characterization of Chemical Interactions between Clinical Drugs and the Oral Bacterium, Corynebacterium matruchotii, via Bioactivity-HiTES

Lee,

Kim,

Lee

et al. 2024

ACS Chem. Biol.

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“…S2.1). The first part (BGC 22_1) encodes a cyclic hexapeptide longicatenamycin B, recently discovered in S. rimosus by Li et al ( 39 ), and the second part (BGC 22_2) encodes a yet unknown NRPS metabolite (AntiSMASH analysis—Fig. S2).…”

Section: Resultsmentioning

confidence: 99%

Oxytetracycline hyper-production through targeted genome reduction of Streptomyces rimosus

Pšeničnik,

Slemc,

Avbelj

et al. 2024

mSystems

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Most biosynthetic gene clusters (BGC) encoding the synthesis of important microbial secondary metabolites, such as antibiotics, are either silent or poorly expressed; therefore, to ensure a strong pipeline of novel antibiotics, there is a need to develop rapid and efficient strain development approaches. This study uses comparative genome analysis to instruct rational strain improvement, using Streptomyces rimosus , the producer of the important antibiotic oxytetracycline (OTC) as a model system. Sequencing of the genomes of two industrial strains M4018 and R6-500, developed independently from a common ancestor, identified large DNA rearrangements located at the chromosome end. We evaluated the effect of these genome deletions on the parental S. rimosus Type Strain (ATCC 10970) genome where introduction of a 145 kb deletion close to the OTC BGC in the Type Strain resulted in massive OTC overproduction, achieving titers that were equivalent to M4018 and R6-500. Transcriptome data supported the hypothesis that the reason for such an increase in OTC biosynthesis was due to enhanced transcription of the OTC BGC and not due to enhanced substrate supply. We also observed changes in the expression of other cryptic BGCs; some metabolites, undetectable in ATCC 10970, were now produced at high titers. This study demonstrated for the first time that the main force behind BGC overexpression is genome rearrangement. This new approach demonstrates great potential to activate cryptic gene clusters of yet unexplored natural products of medical and industrial value. IMPORTANCE There is a critical need to develop novel antibiotics to combat antimicrobial resistance. Streptomyces species are very rich source of antibiotics, typically encoding 20–60 biosynthetic gene clusters (BGCs). However, under laboratory conditions, most are either silent or poorly expressed so that their products are only detectable at nanogram quantities, which hampers drug development efforts. To address this subject, we used comparative genome analysis of industrial Streptomyces rimosus strains producing high titers of a broad spectrum antibiotic oxytetracycline (OTC), developed during decades of industrial strain improvement. Interestingly, large-scale chromosomal deletions were observed. Based on this information, we carried out targeted genome deletions in the native strain S. rimosus ATCC 10970, and we show that a targeted deletion in the vicinity of the OTC BGC significantly induced expression of the OTC BGC, as well as some other silent BGCs, thus suggesting that this approach may be a useful way to identify new natural products.

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“…mycoplanecinus subsp. nov., 36 decatransin isolated from the saprophyte fungus Chaetosphaeria tulasneorum, 37 longicatenamycin B obtained from Streptomyces rimosus, 38 and ulleungmycins A from Streptomyces sp. KCB13F003.…”

Section: Structure Elucidation Of Pseudoviridinutans A−g (1− 7)mentioning

confidence: 99%

Molecular Networking-Guided Isolation of Cyclopentapeptides from the Hydrothermal Vent Sediment Derived Fungus Aspergillus pseudoviridinutans TW58-5 and Their Anti-inflammatory Effects

et al. 2023

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Repetitive isolation of known compounds remains a major challenge in natural-product-based drug discovery. LC-MS/MS-based molecular networking has become a highly efficient strategy for the discovery of new natural products from complex mixtures. Herein, we report a molecular networking-guided isolation procedure, which resulted in the discovery of seven new cyclopentapeptides, namely, pseudoviridinutans A−F (1−7), from the marine-derived fungus Aspergillus pseudoviridinutans TW58-5. Compounds 1−7 feature a rare amino acid moiety, O,β-dimethyltyrosine, observed for the first time from a marine-derived fungus. The planar structures of 1−7 were elucidated by detailed analyses of IR, UV, HR ESI-Q-TOF MS, and 1D and 2D NMR spectroscopic data. Meanwhile, their absolute configurations were determined through a combination of Marfey's method and X-ray diffraction. Subsequent bioassay revealed the antiinflammation potential of 1−7, especially 6, which inhibited the production of nitric oxide (NO), a vital inflammatory mediator, in LPS-induced murine macrophage RAW264.7 cells by regulating the expression level of NLRP3 and iNOS.

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Momomycin, an Antiproliferative Cryptic Metabolite from the Oxytetracycline Producer Streptomyces rimosus

Cited by 13 publications

References 63 publications

Characterization of Chemical Interactions between Clinical Drugs and the Oral Bacterium, Corynebacterium matruchotii, via Bioactivity-HiTES

Characterization of Chemical Interactions between Clinical Drugs and the Oral Bacterium, Corynebacterium matruchotii, via Bioactivity-HiTES

Oxytetracycline hyper-production through targeted genome reduction of Streptomyces rimosus

Molecular Networking-Guided Isolation of Cyclopentapeptides from the Hydrothermal Vent Sediment Derived Fungus Aspergillus pseudoviridinutans TW58-5 and Their Anti-inflammatory Effects

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