Introduction of a terminal hydroxy group into the lipid part of a moenomycin-type transglycosylase inhibitor suppresses antibiotic activity

Kempin, Uwe; Hennig, Lothar; Welzel, Peter; Marzian, Susanne; Müller, D.; Fehlhaber, H.‐W.; Markus, A.; Heijenoort, Yveline van; Heijenoort, Jean van

doi:10.1016/0040-4020(95)00462-h

Cited by 25 publications

(12 citation statements)

References 25 publications

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“…The presence of a long lipid chain on moenomycin has been shown to be essential for good antimicrobial activity (26,27). To assess the role of the lipid chain in enzyme inhibition, we tested the delipidated moenomycin derivative 8.…”

Section: Resultsmentioning

confidence: 99%

Vancomycin analogues active against vanA-resistant strains inhibit bacterial transglycosylase without binding substrate

Chen

Walker

Sun

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

140

147

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Bacterial transglycosylases are enzymes that couple the disaccharide subunits of peptidoglycan to form long carbohydrate chains. These enzymes are the target of the pentasaccharide antibiotic moenomycin as well as the proposed target of certain glycopeptides that overcome vancomycin resistance. Because bacterial transglycosylases are difficult enzymes to study, it has not previously been possible to evaluate how moenomycin inhibits them or to determine whether glycopeptide analogues directly target them. We have identified transglycosylase assay conditions that enable kinetic analysis of inhibitors and have examined the inhibition of Escherichia coli penicillin-binding protein 1b (PBP1b) by moenomycin as well as by various glycopeptides. We report that chlorobiphenyl vancomycin analogues that are incapable of binding substrates nevertheless inhibit E. coli PBP1b, which shows that these compounds interact directly with the enzyme. These findings support the hypothesis that chlorobiphenyl vancomycin derivatives overcome vanA resistance by targeting bacterial transglycosylases. We have also found that moenomycin is not competitive with respect to the lipid II substrate of PBP1b, as has long been believed. With the development of suitable methods to evaluate bacterial transglycosylases, it is now possible to probe the mechanism of action of some potentially very important antibiotics.

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Section: Resultsmentioning

confidence: 99%

Vancomycin analogues active against vanA-resistant strains inhibit bacterial transglycosylase without binding substrate

Chen

Walker

Sun

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

140

147

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“…Furthermore, a moenomycin A carrying an oxygen in the moenocinol-group was found, which is most probably a chemical degradation product. This compound is assumed to have a comparable low, if any, antibiotic activity [48].…”

Section: Discussionmentioning

confidence: 99%

Characterization of moenomycin antibiotic complex by multistage MALDI-IT/RTOF-MS and ESI-IT-MS

Zehl

Pittenauer

Rizzi

et al. 2006

J. Am. Soc. Mass Spectrom.

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Flavomycin is a commercially available antimicrobial growth promoter and an authorized additive for feeding stuffs in the EU and in the USA. As most antibiotically active products biosynthesized by microorganisms, it contains not only a single active compound but is a complex mixture of structurally closely related substances. Multistage matrix-assisted laser desorption/ionization-ion trap/reflectron time-of-flight mass spectrometry (MALDI-IT/ RTOF-MS) and liquid chromatography-electrospray ionization-ion trap-mass spectrometry (LC-ESI-IT-MS) were utilized for a detailed analysis of the constituents of the Flavomycin complex based on low-energy collision induced dissociation (CID). An optimal sample preparation for negative ion vacuum MALDI-MS for this compound class was developed. The MALDI-IT/RTOF-MS 2 and -MS 3 analysis starting with the precursor [M Ϫ H] Ϫ ions of these interesting phosphoglycolipids, named moenomycins, yielded a large variety of product ions that facilitated the structural characterization of this class of compounds. Based on the derived CID fragmentation pathway of the five known major constituents, namely moenomycin A, moenomycin A 12 , moenomycin C 4 , moenomycin C 3 . and moenomycin C 1 , four not yet described moenomycin-type constituents could be characterized. They were assigned as 4F-demethyl-6E-O-de-␤-D-glucopyranosyl-moenomycin A, 6B-N-de(2-hydroxy-5-oxo-1-cyclopenten-1-yl)-moenomycin A, 6B-hydroxy-6B-de[N-(2-hydroxy-5-oxo-1-cyclopenten-1-yl)amino]-moenomycin A, and 6C-hydroxy-moenomycin A. In addition, a moenomycin A carrying an oxygen in the moenocinol-group was found, which is most probably a chemical degradation product. These new compounds were verified by LC-ESI-IT-MS. (J Am Soc Mass

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“…'^ (in Ref. 13, the numbering of C-19 and C-20 should be reversed). Also, the proton signals of units F and D could be nicely assigned using the TOCSY and H,H COSY spectra.…”

Section: Results a N D Discussionmentioning

confidence: 99%

1H NMR as a Tool for the Structure Elucidation of Moenomycin Antibiotics

Donnerstag¹,

Hennig²,

Findeisen³

et al. 1996

Magn. Reson. Chem.

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Introduction of a terminal hydroxy group into the lipid part of a moenomycin-type transglycosylase inhibitor suppresses antibiotic activity

Cited by 25 publications

References 25 publications

Vancomycin analogues active against vanA-resistant strains inhibit bacterial transglycosylase without binding substrate

Vancomycin analogues active against vanA-resistant strains inhibit bacterial transglycosylase without binding substrate

Characterization of moenomycin antibiotic complex by multistage MALDI-IT/RTOF-MS and ESI-IT-MS

1H NMR as a Tool for the Structure Elucidation of Moenomycin Antibiotics

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