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Opportunities for synthetic biology in antibiotics: expanding glycopeptide chemical diversity.

Thaker MN, Wright GD - ACS Synth Biol (2012)

Bottom Line: All antibiotics in clinical use are facing eventual obsolesce as a result of the evolution and dissemination of resistance mechanisms, yet there are few new drug leads forthcoming from the pharmaceutical sector.Natural products of microbial origin have proven over the past 70 years to be the wellspring of antimicrobial drugs.We review these strategies here using the glycopeptides as an example and demonstrate how synthetic biology can expand antibiotic chemical diversity to help address the growing resistance crisis.

View Article: PubMed Central - PubMed

Affiliation: M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1 Canada.

ABSTRACT
Synthetic biology offers a new path for the exploitation and improvement of natural products to address the growing crisis in antibiotic resistance. All antibiotics in clinical use are facing eventual obsolesce as a result of the evolution and dissemination of resistance mechanisms, yet there are few new drug leads forthcoming from the pharmaceutical sector. Natural products of microbial origin have proven over the past 70 years to be the wellspring of antimicrobial drugs. Harnessing synthetic biology thinking and strategies can provide new molecules and expand chemical diversity of known antibiotic scaffolds to provide much needed new drug leads. The glycopeptide antibiotics offer paradigmatic scaffolds suitable for such an approach. We review these strategies here using the glycopeptides as an example and demonstrate how synthetic biology can expand antibiotic chemical diversity to help address the growing resistance crisis.

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Related in: MedlinePlus

The diversity of GPAmodifications offers tremendous opportunityfor chemical diversification. The GPA heptapeptide backbone is numbered,and arcs represent regions of cross-linking. (A) Sites of primarymodification of the backbone in the form of halogenation, glycosylation,methylation, and sulfation. Homologues of the modifying enzymes acton one or more different amino acid as indicated. (B) Secondary modificationsare confined to the Hpg4 sugar (glucose or GlcNAc) in theform of methylation, acylation, or glycosylation.
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fig6: The diversity of GPAmodifications offers tremendous opportunityfor chemical diversification. The GPA heptapeptide backbone is numbered,and arcs represent regions of cross-linking. (A) Sites of primarymodification of the backbone in the form of halogenation, glycosylation,methylation, and sulfation. Homologues of the modifying enzymes acton one or more different amino acid as indicated. (B) Secondary modificationsare confined to the Hpg4 sugar (glucose or GlcNAc) in theform of methylation, acylation, or glycosylation.

Mentions: Various tailoring enzymes includingglycosyltransferases, methyltransferases,sulfotransferases, halogenases, and acyltransferases decorate theheptapeptide scaffolds of GPAs. The modifications resulting from theaction of these enzymes have been shown or speculated to impart stability,increase solubility, affect dimerization constants, limit conformationalflexibility, avoid degradation, and evade resistance.34−37 GPA tailoring modifications can be grouped in two categories: (1)primary modifications, where the amino acid components of the GPAscaffold are directly modified (Figure 6A),and (2) secondary modifications, referring to tailoring of primarymodifications (Figure 6B). Thus, the presenceof a primary modification of the amino acid is a prerequisite forthe action of this latter group of enzymes.


Opportunities for synthetic biology in antibiotics: expanding glycopeptide chemical diversity.

Thaker MN, Wright GD - ACS Synth Biol (2012)

The diversity of GPAmodifications offers tremendous opportunityfor chemical diversification. The GPA heptapeptide backbone is numbered,and arcs represent regions of cross-linking. (A) Sites of primarymodification of the backbone in the form of halogenation, glycosylation,methylation, and sulfation. Homologues of the modifying enzymes acton one or more different amino acid as indicated. (B) Secondary modificationsare confined to the Hpg4 sugar (glucose or GlcNAc) in theform of methylation, acylation, or glycosylation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384835&req=5

fig6: The diversity of GPAmodifications offers tremendous opportunityfor chemical diversification. The GPA heptapeptide backbone is numbered,and arcs represent regions of cross-linking. (A) Sites of primarymodification of the backbone in the form of halogenation, glycosylation,methylation, and sulfation. Homologues of the modifying enzymes acton one or more different amino acid as indicated. (B) Secondary modificationsare confined to the Hpg4 sugar (glucose or GlcNAc) in theform of methylation, acylation, or glycosylation.
Mentions: Various tailoring enzymes includingglycosyltransferases, methyltransferases,sulfotransferases, halogenases, and acyltransferases decorate theheptapeptide scaffolds of GPAs. The modifications resulting from theaction of these enzymes have been shown or speculated to impart stability,increase solubility, affect dimerization constants, limit conformationalflexibility, avoid degradation, and evade resistance.34−37 GPA tailoring modifications can be grouped in two categories: (1)primary modifications, where the amino acid components of the GPAscaffold are directly modified (Figure 6A),and (2) secondary modifications, referring to tailoring of primarymodifications (Figure 6B). Thus, the presenceof a primary modification of the amino acid is a prerequisite forthe action of this latter group of enzymes.

Bottom Line: All antibiotics in clinical use are facing eventual obsolesce as a result of the evolution and dissemination of resistance mechanisms, yet there are few new drug leads forthcoming from the pharmaceutical sector.Natural products of microbial origin have proven over the past 70 years to be the wellspring of antimicrobial drugs.We review these strategies here using the glycopeptides as an example and demonstrate how synthetic biology can expand antibiotic chemical diversity to help address the growing resistance crisis.

View Article: PubMed Central - PubMed

Affiliation: M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1 Canada.

ABSTRACT
Synthetic biology offers a new path for the exploitation and improvement of natural products to address the growing crisis in antibiotic resistance. All antibiotics in clinical use are facing eventual obsolesce as a result of the evolution and dissemination of resistance mechanisms, yet there are few new drug leads forthcoming from the pharmaceutical sector. Natural products of microbial origin have proven over the past 70 years to be the wellspring of antimicrobial drugs. Harnessing synthetic biology thinking and strategies can provide new molecules and expand chemical diversity of known antibiotic scaffolds to provide much needed new drug leads. The glycopeptide antibiotics offer paradigmatic scaffolds suitable for such an approach. We review these strategies here using the glycopeptides as an example and demonstrate how synthetic biology can expand antibiotic chemical diversity to help address the growing resistance crisis.

Show MeSH
Related in: MedlinePlus