Quinovosamycins: new tunicamycin-type antibiotics in which the α, β-1″,11′-linked N-acetylglucosamine residue is replaced by N-acetylquinovosamine

Price, Neil P. J.; Labeda, David P.; Naumann, Todd A.; Vermillion, Karl E.; Bowman, Michael J.; Berhow, Mark A.; Metcalf, William W.; Bischoff, Kenneth M.

doi:10.1038/ja.2016.49

Cited by 11 publications

(11 citation statements)

References 53 publications

(68 reference statements)

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“…Interestingly, the inhibition of CbMraY as determined by the FRET-based activity assay is remarkably reduced by the modification, where QVM 16:1 ( iso ) is almost 100-fold less potent compared to the corresponding tunicamycin variant Tun 16:1 ( iso ). It has previously been shown that QVM inhibits S. cerevisiae GPT as potently as tunicamycin (MIC value of 0.25 μL/ml for both compounds) in a broth dilution assay . Hence, removal of the hydroxyl group on the 6″-carbon of the tunicamycin GlcNAc has a significantly different effect on MraY inhibition as compared to GPT inhibition.…”

Section: Resultssupporting

confidence: 92%

“…The uracil ring-opened analog (TunR3) was prepared by base-catalyzed hydrolysis of TunR2 . Quinovosamycins were isolated from Streptomyces niger NRRL B-3857 as described . The compounds were purified by reversed-phase HPLC on a Finnigan Surveyor instrument (ThermoFisher Scientific, West Palm Beach, FL, USA) using a specialized C 30 column typically used to purify long-chain carotenes (YMC Carotene C-30, 3 μm particle size, 4.6 × 250 mm).…”

Section: Methodsmentioning

confidence: 99%

“…Homologues of tunicamycin can occur with different chain length N -acyl groups, and these fatty acyl chains can be further defined in terms of their terminal branching, either iso -, anteiso -, or unbranched − (this paper, Figure A). Variants of the typical tunicamycins have been reported including the quinovosamycins (QVM) produced by S. niger where the GlcNAc motif is replaced with QuiNAc (Figure B) . It has been shown that tunicamycin and QVM display similar minimum inhibitory concentration (MIC) values against the eukaryotic model system Saccharomyces cerevisiae , whereas tunicamycin is ∼10-fold more potent than QVM against Bacillus subtilis bacteria …”

Section: Introductionmentioning

confidence: 99%

“…Variants of the typical tunicamycins have been reported including the quinovosamycins (QVM) produced by S. niger where the GlcNAc motif is replaced with QuiNAc (Figure B) . It has been shown that tunicamycin and QVM display similar minimum inhibitory concentration (MIC) values against the eukaryotic model system Saccharomyces cerevisiae , whereas tunicamycin is ∼10-fold more potent than QVM against Bacillus subtilis bacteria …”

Section: Introductionmentioning

confidence: 99%

“…Variants of the typical tunicamycins have been reported including the quinovosamycins (QVM) produced by S. niger where the GlcNAc motif is replaced with QuiNAc (Figure 2B). 17 It has been shown that tunicamycin and QVM display similar minimum inhibitory concentration (MIC) values against the eukaryotic model system Saccharomyces cerevisiae, whereas tunicamycin is ∼10-fold more potent than QVM against Bacillus subtilis bacteria. 17 An important biological effect of tunicamycin initially reported by Walker et al is the dramatic synergy observed with β-lactam antibiotics, 18 although it has also been pointed out that natural tunicamycin is too toxic for clinical use.…”

Section: ■ Introductionmentioning

confidence: 99%

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Exploring the Active Site of the Antibacterial Target MraY by Modified Tunicamycins

et al. 2020

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The alarming growth of antibiotic resistance that is currently ongoing is a serious threat to human health. One of the most promising novel antibiotic targets is MraY (phospho-MurNAc-pentapeptide-transferase), an essential enzyme in bacterial cell wall synthesis. Through recent advances in biochemical research, there is now structural information available for MraY, and for its human homologue GPT (GlcNAc-1-P-transferase), that opens up exciting possibilities for structure-based drug design. The antibiotic compound tunicamycin is a natural product inhibitor of MraY that is also toxic to eukaryotes through its binding to GPT. In this work, we have used tunicamycin and modified versions of tunicamycin as tool compounds to explore the active site of MraY and to gain further insight into what determines inhibitor potency. We have investigated tunicamycin variants where the following motifs have been modified: the length and branching of the tunicamycin fatty acyl chain, the saturation of the fatty acyl chain, the 6″hydroxyl group of the GlcNAc ring, and the ring structure of the uracil motif. The compounds are analyzed in terms of how potently they bind to MraY, inhibit the activity of the enzyme, and affect the protein thermal stability. Finally, we rationalize these results in the context of the protein structures of MraY and GPT.

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Section: Resultssupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Exploring the Active Site of the Antibacterial Target MraY by Modified Tunicamycins

et al. 2020

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Analysis of Carbohydrates and Glycoconjugates by Matrix‐assisted Laser Desorption/Ionization Mass Spectrometry: An Update for 2015–2016

Harvey

2021

Mass Spectrometry Reviews

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This review is the ninth update of the original article published in 1999 on the application of matrix‐assisted laser desorption/ionization (MALDI) mass spectrometry to the analysis of carbohydrates and glycoconjugates and brings coverage of the literature to the end of 2016. Also included are papers that describe methods appropriate to analysis by MALDI, such as sample preparation techniques, even though the ionization method is not MALDI. Topics covered in the first part of the review include general aspects such as theory of the MALDI process, matrices, derivatization, MALDI imaging, fragmentation and arrays. The second part of the review is devoted to applications to various structural types such as oligo‐ and poly‐saccharides, glycoproteins, glycolipids, glycosides and biopharmaceuticals. Much of this material is presented in tabular form. The third part of the review covers medical and industrial applications of the technique, studies of enzyme reactions and applications to chemical synthesis. The reported work shows increasing use of combined new techniques such as ion mobility and the enormous impact that MALDI imaging is having. MALDI, although invented over 30 years ago is still an ideal technique for carbohydrate analysis and advancements in the technique and range of applications show no sign of deminishing. © 2020 Wiley Periodicals, Inc.

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Phylogenetic relationships in the family Streptomycetaceae using multi-locus sequence analysis

Labeda

Dunlap

Rong

et al. 2016

Antonie van Leeuwenhoek

145

112

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The family Streptomycetaceae, notably species in the genus Streptomyces, have long been the subject of investigation due to their well-known ability to produce secondary metabolites. The emergence of drug resistant pathogens and the relative ease of producing genome sequences has renewed the importance of Streptomyces as producers of new natural products and resulted in revived efforts in isolating and describing strains from novel environments. A previous large study of the phylogeny in the Streptomycetaceae based on 16S rRNA gene sequences provided a useful framework for the relationships among species, but did not always have sufficient resolution to provide definitive identification. Multi-locus sequence analysis of 5 house-keeping genes has been shown to provide improved taxonomic resolution of Streptomyces species in a number of previous reports so a comprehensive study was undertaken to evaluate evolutionary relationships among species within the family Streptomycetaceae where type strains are available in the ARS Culture Collection or genome sequences are available in GenBank. The results of the analysis supported the distinctiveness of Kitasatospora and Streptacidiphilus as validly named genera since they cluster outside of the phylogenetic radiation of the genus Streptomyces. There is also support for the transfer of a number of Streptomyces species to the genus Kitasatospora as well for reducing at least 31 species clusters to a single taxon. The multi-locus sequence database resulting from the study is a useful tool for identification of new isolates and the phylogenetic analysis presented also provides a road map for planning future genome sequencing efforts in the Streptomycetaceae.

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Quinovosamycins: new tunicamycin-type antibiotics in which the α, β-1″,11′-linked N-acetylglucosamine residue is replaced by N-acetylquinovosamine

Cited by 11 publications

References 53 publications

Exploring the Active Site of the Antibacterial Target MraY by Modified Tunicamycins

Exploring the Active Site of the Antibacterial Target MraY by Modified Tunicamycins

Analysis of Carbohydrates and Glycoconjugates by Matrix‐assisted Laser Desorption/Ionization Mass Spectrometry: An Update for 2015–2016

Phylogenetic relationships in the family Streptomycetaceae using multi-locus sequence analysis

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