3-Keto-11,12-carbazate Derivatives of 6-0-Methylerythromycin A Synthesis and In Vitro Activity.

Griesgraber, George; Or, Yat Sun; Chu, Daniel T. W.; Nilius, Angela M.; Johnson, Pauline M.; Flamm, Robert K.; Henry, Rodger F.; Plattner, Jacob J.

doi:10.7164/antibiotics.49.465

Cited by 42 publications

(42 citation statements)

References 9 publications

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“…Ketolides (10), characterized by a 3-ketone functionality, are a new class of semisynthetic macrolides which have shown excellent in vitro antibacterial activity against macrolide-resistant pathogens (18,27,28). These compounds are currently prepared from erythromycin by a complex multistep chemical synthesis.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Macrolide P-450 Hydroxylase from Streptomyces venezuelae Which Converts Narbomycin to Picromycin^,

Betlach¹,

Kealey²,

Ashley³

et al. 1998

Biochemistry

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The post-polyketide synthase (PKS) biosynthetic tailoring of macrolide antibiotics usually involves one or more oxidation reactions catalyzed by cytochrome P450 monooxygenases. As the specificities of members from this class of enzymes vary significantly among PKS gene clusters, the identification and study of new macrolide P450s are important to the growing field of combinatorial biosynthesis. We have isolated the cytochrome P450 gene picK from Streptomyces venezuelae which is responsible for the C-12 hydroxylation of narbomycin to picromycin. The gene was located by searching regions proximal to modular PKS genes with a probe for macrolide P450 monooxygenases. The overproduction of PicK with a C-terminal six-His affinity tag (PicK/6-His) in Escherichia coli aided the purification of the enzyme for kinetic analysis. PicK/6-His was shown to catalyze the in vitro C-12 hydroxylation of narbomycin with a kcat of 1.4 s-1, which is similar to the value reported for the related C-12 hydroxylation of erythromycin D by the EryK hydroxylase. The unique specificity of this enzyme should be useful for the modification of novel macrolide substrates similar to narbomycin, in particular, ketolides, a promising class of semisynthetic macrolides with activity against erythromycin-resistant pathogens.

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Section: Discussionmentioning

confidence: 99%

Characterization of the Macrolide P-450 Hydroxylase from Streptomyces venezuelae Which Converts Narbomycin to Picromycin^,

Betlach¹,

Kealey²,

Ashley³

et al. 1998

Biochemistry

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“…The above situation has resulted in the development of further macrolides with which to address the problems of resistance [24]. In recent work reported by Rousel Uclaf, a new distinct class of 14-membered macrolides was discovered, characterised by replacement of the cladinose moiety of erythromycin with a 3 keto-function [24]. This compound, referred to as a ketolide, was optimised by further modification to produce a series of ketolides demonstrating activity against macrolide-resistant organisms [24].…”

Section: Ketolidesmentioning

confidence: 98%

“…In recent work reported by Rousel Uclaf, a new distinct class of 14-membered macrolides was discovered, characterised by replacement of the cladinose moiety of erythromycin with a 3 keto-function [24]. This compound, referred to as a ketolide, was optimised by further modification to produce a series of ketolides demonstrating activity against macrolide-resistant organisms [24]. Currently, one of the most promising ketolides is RU64004 (Figure 2; 3) for which preclinical data have recently been reported [25].…”

Section: Ketolidesmentioning

confidence: 99%

“…Unfortunately, clarithromycin and azithromycin, like erythromycin and other 14-membered macrolides, have relatively poor activity against macrolideresistant bacteria in which resistance results from plasmid and transposon-mediated methylation of 23S rRNA (MLS phenotype) [23][24][25]. The above situation has resulted in the development of further macrolides with which to address the problems of resistance [24]. In recent work reported by Rousel Uclaf, a new distinct class of 14-membered macrolides was discovered, characterised by replacement of the cladinose moiety of erythromycin with a 3 keto-function [24].…”

Section: Ketolidesmentioning

confidence: 99%

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Protein synthesis as a target for antibacterial drugs: current status and future opportunities

Chopra

1998

Expert Opinion on Investigational Drugs

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The discovery and development of clinically useful antibiotic classes, such as the aminoglycosides, macrolides and tetracyclines, have clearly demonstrated that bacterial protein synthesis is a suitable target for drug intervention. New information on the binding of classical protein synthesis inhibitors to ribosomal RNA provides a rational explanation for their selective action against bacteria and also explains why chromosomal point mutations conferring resistance by structural changes at the target site are relatively rare in the majority of bacteria. These principles will be helpful when considering strategies for the screening or design of novel protein synthesis inhibitors that could be developed as new antibiotics. Recent progress in the discovery and development of bacterial protein synthesis inhibitors is illustrated by consideration of the glycylcyclines, ketolides, oxazolidinones and streptogramins.

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“…This compound was reduced by catalytic hydrogenation to give amine 30, which underwent the EschweilerClarke methylation to provide 6-Omethylazithromycin 31. was obtained as the only product. This compound was reduced with sodium borohydride in ethylene glycol, and the resulting amine 34 was methylated under Eschweiler-Clarke conditions to furnish 6-Omethyl-iso-azithromycin (35 …”

Section: Clarithromycin 9(e)-oximementioning

confidence: 99%

Highlights of Semi-synthetic Developments from Erythromycin A

Wu¹

2000

CPD

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Earlier semi-synthetic studies of erythromycin A culminated in the discovery of two successful second generation macrolide antibiotics, azithromycin and clarithromycin, for the treatment of community-acquired bacterial infections. More recent structural modifications of erythromycin A have resulted in the discovery of novel ketolide antibiotics and new motilide prokinetic agents. This review is an account of the semi-synthetic developments from erythromycin A by chemical transformations.

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3-Keto-11,12-carbazate Derivatives of 6-0-Methylerythromycin A Synthesis and In Vitro Activity.

Cited by 42 publications

References 9 publications

Characterization of the Macrolide P-450 Hydroxylase from Streptomyces venezuelae Which Converts Narbomycin to Picromycin^,

Characterization of the Macrolide P-450 Hydroxylase from Streptomyces venezuelae Which Converts Narbomycin to Picromycin^,

Protein synthesis as a target for antibacterial drugs: current status and future opportunities

Highlights of Semi-synthetic Developments from Erythromycin A

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3-Keto-11,12-carbazate Derivatives of 6-0-Methylerythromycin A Synthesis and In Vitro Activity.

Cited by 42 publications

References 9 publications

Characterization of the Macrolide P-450 Hydroxylase from Streptomyces venezuelae Which Converts Narbomycin to Picromycin,

Characterization of the Macrolide P-450 Hydroxylase from Streptomyces venezuelae Which Converts Narbomycin to Picromycin,

Protein synthesis as a target for antibacterial drugs: current status and future opportunities

Highlights of Semi-synthetic Developments from Erythromycin A

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Product

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About

Characterization of the Macrolide P-450 Hydroxylase from Streptomyces venezuelae Which Converts Narbomycin to Picromycin^,

Characterization of the Macrolide P-450 Hydroxylase from Streptomyces venezuelae Which Converts Narbomycin to Picromycin^,