Isolation, structure elucidation, total synthesis, and biosynthesis of dermazolium A, an antibacterial imidazolium metabolite of a vaginal bacterium Dermabacter vaginalis

Kim, Hye Ryeong; Kim, Jonghwan; Yu, Jae Sik; Lee, Bum Soo; Kim, Ki‐Hyun; Kim, Chung Sub

doi:10.1007/s12272-022-01424-z

Cited by 9 publications

(8 citation statements)

References 27 publications

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“…Addition of one more tryptamine molecule to 9a/9b followed by tautomerization would generate intermediate ii , and this would be coupled with formaldehyde (route a) to produce the imidazolium metabolite 2 through iminium formation, cyclization, and oxidation. Compound 1 would be formed by addition of a formaldehyde molecule to 2 or an acetaldehyde molecule to ii (route b) (Figure A) . Compounds 3 and 4 possess an n -propyl and an isobutyl group, respectively, instead of the methyl group in 1 , suggesting that butyraldehyde and isovaleraldehyde derived from l -Leu would couple to ii to generate 3 and 4 , respectively (Figure B).…”

Section: Resultsmentioning

confidence: 99%

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Discovery and Biosynthesis of Imidazolium Antibiotics from the Probiotic Bacillus licheniformis

et al. 2023

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Antibiotic resistance is one of the world's most urgent public health problems, and novel antibiotics to kill drugresistant bacteria are needed. Natural product-derived small molecules have been the major source of new antibiotics. Here we describe a family of antibacterial metabolites isolated from a probiotic bacterium, Bacillus licheniformis. A cross-streaking assay followed by activity-guided isolation yielded a novel antibacterial metabolite, bacillimidazole G, which possesses a rare imidazolium ring in the structure, showing MIC values of 0.7−2.6 μg/mL against human pathogenic Gram-positive and Gram-negative bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and a lipopolysaccharide (LPS)-lacking Acinetobacter baumannii ΔlpxC. Bacillimidazole G also lowered MICs of colistin, a Gram-negative antibiotic, up to 8-fold against wild-type Escherichia coli MG1655 and A. baumannii. We propose a biosynthetic pathway to the characterized metabolites based on precursor-feeding studies, a chemical biological approach, biomimetic total synthesis, and a biosynthetic gene knockout method.

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Section: Resultsmentioning

confidence: 99%

“…Each experiment was performed three times. The plate was incubated at 37 °C in a standing incubator overnight, and the MIC value of each compound was acquired from the well where the bacteria were not alive as determined visually …”

Section: Methodsmentioning

confidence: 99%

Discovery and Biosynthesis of Imidazolium Antibiotics from the Probiotic Bacillus licheniformis

et al. 2023

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“…Yellowish gum; UV (MeCN/H 2 O) λ max 220, 280 nm; 1 H (CD 3 OD, 700 MHz) δ 7.51 (1H, dt, J = 7.96, 1.00 Hz, H-7), 7.34 (1H, dt, J = 8.16, 0.95 Hz, H-4), 7.16 (1H, s, H-2), 7.10 (1H, ddd, J = 8.09, 6.93, 1.17 Antibacterial Activity Test of ACR (3), MIAA (4), IAA (5), and F-Ade (6). 41,42 The antibacterial activities of MIAA (4) and IAA (5) were examined against two Gram-negative bacterial strains (E. coli MG1655 and A. baumannii) and three Gram-positive bacterial strains (M. conceptionense, B. subtilis 168, and S. aureus USA300). Additionally, the antibacterial activities of ACR (3) and F-Ade (6) were evaluated against the same strains except for M. conceptionense.…”

Section: ■ Conclusionmentioning

confidence: 99%

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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“…However, even if the NMR data are completely interpreted, the full structural characterization is sometimes not possible due to missing information on connectivity among substructures and/or stereochemistry. This issue is exacerbated when isolated/synthesized compounds have a low H/C ratio (e.g., flavonoids, anthraquinones, tetracyclines). − One of the alternative methods to propose the structure of compounds is the computational chemistry approach, and it has been successful in the structural determination and revision of organic molecules for the last few decades. − …”

Section: Introductionmentioning

confidence: 99%

“…This issue is exacerbated when isolated/synthesized compounds have a low H/C ratio (e.g., flavonoids, anthraquinones, tetracyclines). 1 − 3 One of the alternative methods to propose the structure of compounds is the computational chemistry approach, and it has been successful in the structural determination and revision of organic molecules for the last few decades. 4 − 8 …”

Section: Introductionmentioning

confidence: 99%

Structure Revision of Anti-Inflammatory Indole Alkaloids with a 1,2-Benzisoxazole Ring

et al. 2023

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R)-and (S)-2-(benzo [d]isoxazol-3-yl)-2-ethylindolin-3-one [(±)-1] were previously isolated from NIRAM, a natural blue dye from Polygonum tinctorium, and their structures were initially proposed to possess a 1,2-benzisoxazole ring. In this study, the structures of (±)-1 were revised to have an indole− anthranilic acid fused tetracyclic ring rather than the 1,2benzisoxazole ring by reanalysis of one-dimensional (1D) and two-dimensional (2D) NMR followed by density functional theory (DFT) chemical shift calculation, DP4+ technique, and ECD simulation.

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Isolation, structure elucidation, total synthesis, and biosynthesis of dermazolium A, an antibacterial imidazolium metabolite of a vaginal bacterium Dermabacter vaginalis

Cited by 9 publications

References 27 publications

Discovery and Biosynthesis of Imidazolium Antibiotics from the Probiotic Bacillus licheniformis

Discovery and Biosynthesis of Imidazolium Antibiotics from the Probiotic Bacillus licheniformis

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

Structure Revision of Anti-Inflammatory Indole Alkaloids with a 1,2-Benzisoxazole Ring

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