Synthesis of Fluorescent Derivatives of the Antibiotic Moenomycin A

Buchynskyy, Andrij; Kempin, Uwe; Vogel, Stefan; Hennig, Lothar; Findeisen, Matthias; Müller, D.; Giesa, Sabine; Knöll, H.; Welzel, Peter

doi:10.1002/1099-0690(200204)2002:7<1149::aid-ejoc1149>3.0.co;2-h

Cited by 18 publications

(10 citation statements)

References 27 publications

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“…In one approach to such analogs, treatment of 1 with different aryl diazonium salts produced, via a Japp-Klingemann reaction, compounds that contain o-nitrobenzenediazonium ( 33 ) or various substituted triazole moieties (for example, 34-38 ) 82-84 . 34 , featuring a free thiol group, provided access to biotinylated and dansylated analogs 39-41 83, 85, 86. Other triazole derivatives include moenomycin dimers87 as well as analogs fused to an aminocoumarin moiety ( 42 ),88 various fluorescent labels (for example 43 , carrying fluorescein isothiocyanate)85 and ampicillin ( 44) 84.…”

Section: Moenomycins As a Target Of Chemical Synthesis And Degradatmentioning

confidence: 99%

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%

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

2010

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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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“…We coupled 4d to the moenomycin derivative 7b (obtained from moenomycin A via the azo coupling/JappÀKlingemann route as described previously [29]). The bifunctional linker 4-thiocyanatobenzoyl chloride was used for the conjugation reaction.…”

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“…Like 4d, 4e can be attached to any ligand armed with a suitable functional group. We coupled 4e to the moenomycin-derived amine 7a [29] via the squaric acid linker [30 ± 32]. Thus, reaction of 4e with diethyl squarate provided −squaric acid ester amide× 4f (a 3-amino-4-ethoxycyclobut-3-ene-1,2-dione) in 91% yield.…”

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On Penicillin‐Binding Protein 1b Affinity‐Labeling Reagents

Volke

Daghish

Hennig

et al. 2003

Helvetica Chimica Acta

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Dedicated to Professor Duilio Arigoni on the occasion of his 75th birthdayThe synthesis of some 3-aryl-3-(trifluoromethyl)3H-diazirine and benzophenone-based photoaffinity labels is reported. The photolabile group is bound to a scaffold that also accommodates functional groups to which an indicator unit (biotin) and the bioactive ligand can be attached orthogonally. To three of the labels, moenomycin was conjugated with the aim to provide tools for the identification of the moenomycin binding site within the transglycosylase domain of the enzyme PBP 1b. Some preliminary photoaffinity-labeling experiments were carried out.Introduction. ± Peptidoglycan is an essential cell-wall constituent of almost all eubacteria. It is a heteropolymer consisting of glycan strands cross-linked via short peptide chains. The final events of peptidoglycan biosynthesis at the outside of the cytoplasmic membrane are the formation of the macromolecular architecture by two major types of reaction, i) formation of the polysaccharide strands (transglycosylation) and ii) formation of peptide cross-linkages between the glycan chains (transpeptidation) (for review, see [1]). A representation of the transition state of the transglycosylation reaction is shown in Fig. 1, a [2]. Both the glycosyl donor (the growing peptidoglycan chain) and the glycosyl acceptor (the disaccharide-derived lipid II) (see [1]) are attached to the outer face of the cytoplasmic membrane via a C 55 anchor. The transglycosylation reaction is catalyzed by a number of multimodular bifunctional polymerases (that catalyze also the transpeptidation reaction) designated as class-A high-molecular-mass penicillin-binding proteins (PBPs). Of these, PBP 1b from Escherichia coli has been studied in great detail [3]. It comprises 844 amino acid residues and contains a short cytosolic N-terminus, a membrane span, the D198-G435 glycosyl-transferase module, and the Q447-N844 acyl-transferase module. Within the glycosyl-transferase module, Glu233 has been shown to be central to the transglycosylation, and, in the active site of the acyl transferase, Ser510 is essential, the acylation of which forms the basis of the antibiotic properties of the b-lactams. Recently, the soluble extracellular region of PBP 1b from Streptococcus pneumoniae has been expressed and characterized biochemically [4]. From the most-recent kinetic characterization of the E. coli PBP 1b, it was deduced that a doubly charged metal ion bound to the diphosphate group assists departure of the leaving group, whereas the essential Glu233 acts as a base, removing the proton from the 4-OH group of the glycosyl acceptor (see Fig. 1, a) [5].

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Synthesis of Fluorescent Derivatives of the Antibiotic Moenomycin A

Cited by 18 publications

References 27 publications

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

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

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

On Penicillin‐Binding Protein 1b Affinity‐Labeling Reagents

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