Moenomycin A: reactions at the lipid part. New structure-activity relations

Marzian, Susanne; Happel, M. E.; Wagner, Ulrich; Müller, D.; Welzel, Peter; Fehlhaber, H.‐W.; Stark, Andreas M.; Schütz, Hans-Jürgen; Markus, A.; Limbert, M.; Heijenoort, Yveline van; Heijenoort, Jean van

doi:10.1016/s0040-4020(01)80688-8

Cited by 23 publications

(32 citation statements)

References 16 publications

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“…As described in the accompanying study, 9 nosokomycins are structurally related to moenomycins 10 ( Figure 1). Nosokomycin B is identical to the semisynthetic moenomycin A derivative, 11 which lacks the chromophoric cyclopentenone moiety. Furthermore, nosokomycins A and B were recently reported to be biosynthetic intermediates of moenomycin A in a comprehensive set of genetic and enzymatic experiments that illuminated the moenomycin biosynthetic pathway.…”

Section: Discussionmentioning

confidence: 99%

Nosokomycins, new antibiotics discovered in an in vivo-mimic infection model using silkworm larvae. I: Fermentation, isolation and biological properties

et al. 2010

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The in vivo-mimic assay system using silkworm larvae was used as a screening tool to discover antibiotics against methicillinresistant Staphylococcus aureus (MRSA). Microbial culture broths were screened in this in vivo-mimic assay system and a culture broth of Streptomyces sp. K04-0144 was selected. New antibiotics, designated nosokomycins A-D, were isolated from the culture broth by HP-20 and ODS column chromatography and HPLC. Nosokomycins inhibited the growth of MRSA with MIC values of 0.125 lg ml À1 using the liquid microdilution method. Furthermore, MRSA-infected silkworms survived when nosokomycin A or B was injected at a dose of 50 lg per larva.

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Section: Discussionmentioning

confidence: 99%

Nosokomycins, new antibiotics discovered in an in vivo-mimic infection model using silkworm larvae. I: Fermentation, isolation and biological properties

et al. 2010

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“…Thus, a lipid chain having only ten carbons (15) is sufficient for enzyme inhibition in a membrane-and detergent-free assay, but a longer chain is required for biological activity. Access to the transglycosylases, which are anchored to the bacterial membrane and operate on membrane-bound substrates, may require that moenomycin partition into membranes 3,7,15 . Whether the entire C25 chain is necessary for activity remains to be established.…”

Section: Nih Public Accessmentioning

confidence: 99%

Degradation and Reconstruction of Moenomycin A and Derivatives: Dissecting the Function of the Isoprenoid Chain

et al. 2006

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Moenomycin A is the only known natural product that inhibits peptidoglycan biosynthesis by binding the bacterial transglycosylases. We describe a degradation/reconstruction route to manipulate the reducing end of moenomycin A. A comparision of the biological and enzyme inhibitory activity of moenomycin and an analog containing a nerol lipid in place of the natural C 25 lipid chain provides insight into the role of the moenocinol unit. Our results show that a lipid chain having ten carbons in moenocinol is sufficient for enzyme inhibition, but a longer chain is required for biological acitivity, apparently because the molecule must partition into biological membranes to reach its target in bacterial cells.Moenomycin A (1, Scheme 1) is a natural product that inhibits peptidoglycan biosynthesis by binding to the bacterial transglycosylases (TGases). 1 On a molar basis, moenomycin is a thousand times more potent than vancomycin, but poor pharmacokinetic properties related to the C25 isoprenoid chain have prevented its use in humans. 2 Removing this unit completely abolishes biological activity. 3 Whether this portion of the molecule can be replaced by a shorter lipid is unclear for two reasons: first, until now there have been no methods to remove the natural lipid chain and replace it with other lipids without also altering other structural features of the molecule; 4 second, assays to evaluate the TGase activity of moenomycin and derivatives in the absence of biological membranes 5 have only recently become available 6 , making it difficult to dissect the contribution of the isoprenoid chain to enzyme binding versus membrane anchoring 7 . Here we describe a degradation/ reconstruction route to manipulate the reducing end of moenomycin. We evaluate the enzyme inhibitory activity of moenomycin and an analog containing a nerol chain against kahne@chemistry.harvard.edu. Supporting Information Available: Experimental procedures and spectral data for all compounds. Over-expression and purification conditions for E. faecalis PBP2a are also described. This material is available free of charge via the Internet at http://pubs.acs.org. We faced three challenges in developing a degradation/reconstruction route to moenomycin A. First, although there has been considerable work on the degradation of moenomycin A, 8 a synthetic route to degrade 1 to the intact pentasaccharide 3 has not been reported. Second, we needed to develop a synthesis of the 2-O-moenocinyl glycerate (11, Scheme 2). Model systems for the lipid glycerate have been synthesized previously, but the chemistry could not be extended to the natural lipid. 9 Third, we needed an efficient method to form the phosphoglycerate linkage to 3. NIH Public AccessPrevious studies on the degradation of moenomycin A have shown that under protic acid conditions the glycosidic bonds of the pentasaccharide core begin to decompose before the anomeric phosphate bond is cleaved. 8a We envisioned a solution to this problem that takes advantage of the known lability of allyl et...

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“…Nosokomycin B (2), which lacks the chromophoric cyclopentenone moiety (A), was identical to the semisynthetic moenomycin A derivative. 6 However, 2 was isolated as a main product from Streptomyces sp. K04-0144.…”

Section: Discussionmentioning

confidence: 99%

“…8 However, the structures of only a few members have been fully elucidated. 5 From the structure-activity relationship of moenomycin derivatives reported previously, it has been found that moenomycin trisaccharides containing units C, E, F, G, H and I are the smallest cores to show antibiotic activity in vivo, 6 whereas moenomycin disaccharides containing units E-I still function as transglycosylase inhibitors in vitro. 9 Nosokomycins are larger than the smallest cores of in vivo-active moenomycin derivatives and are also smaller than moenomycin A itself.…”

Section: Discussionmentioning

confidence: 99%

“…2 was identified with the semisynthetic moenomycin derivative. 6 Very recently, a biosynthetic intermediate was found by mass and MS 2 fragmentation data. 7 Structure elucidation of nosokomycin A (1) The molecular formula of 1 was determined by HR-ESI-MS to be C 64 H 103 N 4 O 33 P (found m/z 1485.6206 (M-H) À , calcd 1485.6164) and the results indicated the replacement of NH in 2 with O in 1.…”

Section: Structure Elucidation Of Nosokomycin B (2)mentioning

confidence: 99%

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Nosokomycins, new antibiotics discovered in an in vivo-mimic infection model using silkworm larvae. II: Structure elucidation

et al. 2010

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Moenomycin A: reactions at the lipid part. New structure-activity relations

Cited by 23 publications

References 16 publications

Nosokomycins, new antibiotics discovered in an in vivo-mimic infection model using silkworm larvae. I: Fermentation, isolation and biological properties

Nosokomycins, new antibiotics discovered in an in vivo-mimic infection model using silkworm larvae. I: Fermentation, isolation and biological properties

Degradation and Reconstruction of Moenomycin A and Derivatives: Dissecting the Function of the Isoprenoid Chain

Nosokomycins, new antibiotics discovered in an in vivo-mimic infection model using silkworm larvae. II: Structure elucidation

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