A Long Research Story Culminates in the First Total Synthesis of Moenomycin A

Welzel, Peter

doi:10.1002/anie.200700765

Cited by 15 publications

(9 citation statements)

References 46 publications

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“…Only recently have these challenges been surmounted, culminating after decades of effort in the first total synthesis of 1 (Scheme 3). This achievement, in conjunction with the aforementioned moenomycin degradation-reconstruction approach, deploys a powerful toolkit for chemical synthesis of different types of moenomycin fragments and analogs 60, 99, 100…”

Section: Moenomycins As a Target Of Chemical Synthesis And Degradatmentioning

confidence: 99%

“…This achievement, in conjunction with the aforementioned moenomycin degradation-reconstruction approach, deploys a powerful toolkit for chemical synthesis of different types of moenomycin fragments and analogs. 60,99,100 The oligosaccharide portion of 1 was entirely constructed using sulfoxide glycosylation chemistry, 101,102 although multiple adjustments to (and modifications of) the standard procedure had to be made to stereoselectively generate several of the linkages. 99 The pentasaccharide was built in a modular manner in which disaccharides BC and EF were produced first, then the CE bond was formed between the disaccharides to give the BCEF tetrasaccharide.…”

Section: The Total Synthesis Of Moenomycin Amentioning

confidence: 99%

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Moenomycin family antibiotics: chemical synthesis, biosynthesis, and biological activity

2010

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The review (with 214 references cited) is devoted to moenomycins, the only known group of antibiotics that directly inhibit bacterial peptidoglycan glycosytransferases. Naturally occurring moenomycins and chemical and biological approaches to their derivatives are described. The biological properties of moenomycins and plausible mechanisms of bacterial resistance to them are also covered here, portraying a complete picture of the chemistry and biology of these fascinating natural products

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Section: Moenomycins As a Target Of Chemical Synthesis And Degradatmentioning

confidence: 99%

Section: The Total Synthesis Of Moenomycin Amentioning

confidence: 99%

Moenomycin family antibiotics: chemical synthesis, biosynthesis, and biological activity

2010

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“…Crystal structures of several different PGTs containing MoeA have been reported and show that the compound binds in the same region of the active site where the elongating polymer binds (19–22). The antibiotic activity of MoeA has been attributed to PGT inhibition (23–24), although no resistant mutants containing PGT substitutions have been previously identified to confirm this mechanism (17). In fact, no specific mechanisms for MoeA resistance have been described, although it was suggested that upregulation of PBP genes may help overcome MoeA inhibition (25).…”

Section: Introductionmentioning

confidence: 99%

Moenomycin Resistance Mutations in Staphylococcus aureus Reduce Peptidoglycan Chain Length and Cause Aberrant Cell Division

et al. 2013

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Staphylococcus aureus is a Gram-positive pathogen with an unusual mode of cell division in that it divides in orthogonal rather than parallel planes. Through selection using moenomycin, an antibiotic proposed to target peptidoglycan glycosyltransferases (PGTs), we have generated resistant mutants containing a single point mutation in the active site of the PGT domain of an essential peptidoglycan (PG) biosynthetic enzyme, PBP2. Using cell free polymerization assays, we show that this mutation alters PGT activity so that much shorter PG chains are made. The same mutation in another S. aureus PGT, SgtB, has a similar effect on glycan chain length. Moenomycin-resistant S. aureus strains containing mutated PGTs that make only short glycan polymers display major cell division defects, implicating peptidoglycan chain length in determining bacterial cell morphology and division site placement.

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“…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)(6)(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.…”

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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 Long Research Story Culminates in the First Total Synthesis of Moenomycin A

Cited by 15 publications

References 46 publications

Moenomycin family antibiotics: chemical synthesis, biosynthesis, and biological activity

Moenomycin family antibiotics: chemical synthesis, biosynthesis, and biological activity

Moenomycin Resistance Mutations in Staphylococcus aureus Reduce Peptidoglycan Chain Length and Cause Aberrant Cell Division

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

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