A structurally and biogenetically interesting moenomycin antibiotic

Donnerstag, Astrid; Marzian, Susanne; Müller, D.; Welzel, Peter; Böttger, Dirk; Stark, Andreas M.; Fehlhaber, H.‐W.; Markus, A.; Heijenoort, Yveline van; Heijenoort, Jean van

doi:10.1016/0040-4020(94)01074-a

Cited by 37 publications

(24 citation statements)

References 12 publications

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“…[34] Experimental Section Moenomycin A was a gift from BC Biochemie GmbH (Frankfurt) and was purified prior to use as described previously. [35] 2 6E,13E)-3,8,8, 14,18-pentamethyl-11-methylennonadeca-2,6,13,17-tetraen-1-yloxy)-ethoxy]-hydroxyphosphoryl}-4-C-methyl-a-D-glycopyranuronamide (2): A 40 8C solution (300 mL) of sodium periodate (NaIO 4 ; 1.05 g, 5 mmol) and sodium acetate trihydrate (1.38 g, 10 mmol) in 50 % aqueous acetic acid (12 mL), which had been heated to 80 8C until a clear solution resulted, was added to a solution of 3 (30 mg, 26 mmol) in water (50 mL). The mixture was stirred at 40 8C for 5 h. Excess NaIO 4 was destroyed by addition of ethanediol (15 mL) and stirring at 20 8C for 1 h. At 0 8C a solution of ammonia (25 %, 1 mL) was added and the mixture was stirred at 0 8C for 12 h. After neutralization with acetic acid, the reaction mixture was directly filtered through an LH-20 column (elution with water/ methanol (1:4)).…”

Section: Discussionmentioning

confidence: 99%

A Surface Plasmon Resonance Analysis of the Interaction between the Antibiotic Moenomycin A and Penicillin‐Binding Protein 1b

et al. 2002

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The antibiotic moenomycin A inhibits the biosynthesis of peptidoglycan, the main structural polymer of the bacterial cell wall. The inhibition is based on a reversible binding of the antibiotic to one of the substrate binding sites in enzymes such as penicillin-binding protein (PBP) 1b. A novel assay based on surface plasmon resonance (SPR) has been established that can be used to investigate selective binding of the moenomycin sugar moiety and other transglycosylase inhibitors to this enzyme. Suitable ligands were prepared from moenomycin A and coupled to SPR sensor surfaces. Moenomycin analogues with structural variations were used to perform competitive SPR experiments with PBP 1b. The SPR results confirm for the first time that the trisaccharide fragment of moenomycin A (C-E-F-G-H-I) is the minimal structure that possesses all moieties sufficient for biological activity and for affinity towards PBP 1b. The method seems to be appropriate for use in screens for transglycosylase inhibitors that bind to the moenomycin-binding site of the enzyme.

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Section: Discussionmentioning

confidence: 99%

A Surface Plasmon Resonance Analysis of the Interaction between the Antibiotic Moenomycin A and Penicillin‐Binding Protein 1b

et al. 2002

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“…Moenomycin A 12 [22] also contains the pentasaccharide core with the glucopyranosyl residue (D), but in contrast to moenomycin A, the 4-C-methyl group in the uronamide-derived unit F is absent (Scheme 1). The corresponding [M Ϫ H] Ϫ ion was detected with low abundance at m/z 1566.66 (calc.…”

Section: Moenomycin a 12mentioning

confidence: 99%

“…The moenomycins therefore represent an interesting template for the design of new antibiotic drugs [3,7,8,13,14], which are highly desired because of the problem of bacterial resistance [14 -18]. Now, five major components of the Flavomycin complex have been structurally characterized, namely moenomycin A [19 -21], moenomycin A 12 [22], moenomycin C 4 [23], moenomycin C 3 [23], and moenomycin C 1 [24]. They all consist of a central oligosaccharide part (B-F) that is, on the one side linked to an isoprenoidlike C 25 -alcohol (I) via a phosphodiester group (G) and a 2,3-dihydroxypropanoic acid (glyceric acid) group (H) and, on the other side to a 2-hydroxy-5-oxo-1-cyclopenten-1-yl group (A) (Scheme 1).…”

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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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“…2A) will not dramatically reduce binding and antibacterial activities. Furthermore, the amine moiety in 2 can be conjugated with any fluorophore and used as a probe for binding studies (24,25). Indeed, compound 2 was linked with fluorescein by using 6-carboxyfluorescein N-hydroxysuccinimide ester to prepare the fluorescent probe 3 (F-Moe, Fig.…”

Section: Domain Requirement Of Moenomycin Binding To Class a Pbps (Bimentioning

confidence: 99%

Domain requirement of moenomycin binding to bifunctional transglycosylases and development of high-throughput discovery of antibiotics

Cheng

Sung

Liao

et al. 2008

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

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Moenomycin inhibits bacterial growth by blocking the transglycosylase activity of class A penicillin-binding proteins (PBPs), which are key enzymes in bacterial cell wall synthesis. We compared the binding affinities of moenomycin A with various truncated PBPs by using surface plasmon resonance analysis and found that the transmembrane domain is important for moenomycin binding. Full-length class A PBPs from 16 bacterial species were produced, and their binding activities showed a correlation with the antimicrobial activity of moenomycin against Enterococcus faecalis and Staphylococcus aureus. On the basis of these findings, a fluorescence anisotropy-based high-throughput assay was developed and used successfully for identification of transglycosylase inhibitors.penicillin-binding proteins ͉ transglycosylase inhibitors ͉ fluorescence anisotropy M any common bacterial pathogens, such as Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecalis, have become multidrug-resistant and have emerged as a public health concern, creating an urgent need for new antibiotics.The bacterial cell wall, or its peptidoglycan synthesis pathway, has been targeted for the development of antibacterial agents (1). The synthesis of peptidoglycan consists of several steps, including the formation of lipid I and lipid II, followed by the final transglycosylation and transpeptidation of lipid II to form peptidoglycan (1, 2). Many current antibiotics are ␤-lactam derivatives that target transpeptidation. To our knowledge, no medicines have yet been developed to inhibit the transglycosylation process. The only known potent inhibitors for transglycosylase (TG) are moenomycin complexes (flavomycin), including moenomycin A (Moe A) (Fig. 1A, compound 1), A12, C1, C3, and C4 (3, 4). Among these, Moe A is the most abundant agent in its family (3, 4). The unique antibacterial properties of Moe A have prompted chemists to synthesize moenomycin fragments and derivatives (5-7) in an attempt to develop new antibiotics. Recently, the total synthesis of Moe A (8), and of its biosynthesis pathway (9), has been reported. However, due to poor bioavailability, flavomycin is currently used only as a growth promoter in animal feeds (10).The characterization of class A penicillin-binding proteins (PBPs) and the identification of TG inhibitors require functional PBP and lipid II as the substrate for the enzyme. However, the limited availability of lipid II has hampered the development of effective enzymatic assays for identification of inhibitors. As a result, the majority of the screening methods that are used to search for TG inhibitors, including the low-throughput methods that use surface plasmon resonance (SPR) (12) or radioactive assays (13-16), rely mainly on moenomycin (11). Development of a TG activity assay that is amenable to high-throughput screening (HTS) is thus desirable for inhibitor identification.In this study, we compared the binding of moenomycin to various truncated PBPs and concluded that the transmembrane (TM) domain is c...

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A structurally and biogenetically interesting moenomycin antibiotic

Cited by 37 publications

References 12 publications

A Surface Plasmon Resonance Analysis of the Interaction between the Antibiotic Moenomycin A and Penicillin‐Binding Protein 1b

A Surface Plasmon Resonance Analysis of the Interaction between the Antibiotic Moenomycin A and Penicillin‐Binding Protein 1b

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

Domain requirement of moenomycin binding to bifunctional transglycosylases and development of high-throughput discovery of antibiotics

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