Limits...
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.

Show MeSH
Chemical diversityand complexity of antibiotics in nature. Antibioticsderived from microbial sources are rich in chiral centers and hydrogenbond donors and acceptors and span an order of magnitude in molecularweight.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4384835&req=5

fig1: Chemical diversityand complexity of antibiotics in nature. Antibioticsderived from microbial sources are rich in chiral centers and hydrogenbond donors and acceptors and span an order of magnitude in molecularweight.

Mentions: A hallmark of antibiotic natural products istheir chemical diversityand complexity (Figure 1). This chemical diversityis based on the production of chemical scaffolds consisting of peptide,polyketide, carbohydrate, alkaloid, or terpene backbones that serveas the core structure. These scaffolds are then modified by a varietyof chemical reactions catalyzed by a broad spectrum of tailoring enzymesthat are co-produced with the scaffold assembly machinery. Scaffold-tailoringreactions include isomerization and racemization, reduction and oxidation(including hydroxylation), as well as group transfer such as acylation,methylation, glycosylation, sulfation, phosphorylation, and halogenation.2 As a result the end products are often chemicallycomplex, stereochemically intricate, and rich in hydrogen bond donorsand acceptors. For example, the antibiotic erythromycin has 18 chiralcenters compared to none for the synthetic antibiotic ciprofloxacin.Moreover the macrocyclic polyketide scaffold of erythromycin, 6-deoxyerythronolide,is further modified by glycosylation by two unusual carbohydratesthat contribute to bioactivity and bioavailability to complete theantibiotic. Nature’s ability to generate a large number ofnatural product scaffolds, including the combination of scaffoldsto produce hybrids, and to tailor them in combinatorial fashion resultsin near limitless bioactive chemical diversity. Nevertheless, despitethe proven track record of natural products in drug and antibioticdiscovery, they have largely been abandoned by the pharmaceuticalsector in favor of large libraries of synthetic molecules.


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

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

Chemical diversityand complexity of antibiotics in nature. Antibioticsderived from microbial sources are rich in chiral centers and hydrogenbond donors and acceptors and span an order of magnitude in molecularweight.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Chemical diversityand complexity of antibiotics in nature. Antibioticsderived from microbial sources are rich in chiral centers and hydrogenbond donors and acceptors and span an order of magnitude in molecularweight.
Mentions: A hallmark of antibiotic natural products istheir chemical diversityand complexity (Figure 1). This chemical diversityis based on the production of chemical scaffolds consisting of peptide,polyketide, carbohydrate, alkaloid, or terpene backbones that serveas the core structure. These scaffolds are then modified by a varietyof chemical reactions catalyzed by a broad spectrum of tailoring enzymesthat are co-produced with the scaffold assembly machinery. Scaffold-tailoringreactions include isomerization and racemization, reduction and oxidation(including hydroxylation), as well as group transfer such as acylation,methylation, glycosylation, sulfation, phosphorylation, and halogenation.2 As a result the end products are often chemicallycomplex, stereochemically intricate, and rich in hydrogen bond donorsand acceptors. For example, the antibiotic erythromycin has 18 chiralcenters compared to none for the synthetic antibiotic ciprofloxacin.Moreover the macrocyclic polyketide scaffold of erythromycin, 6-deoxyerythronolide,is further modified by glycosylation by two unusual carbohydratesthat contribute to bioactivity and bioavailability to complete theantibiotic. Nature’s ability to generate a large number ofnatural product scaffolds, including the combination of scaffoldsto produce hybrids, and to tailor them in combinatorial fashion resultsin near limitless bioactive chemical diversity. Nevertheless, despitethe proven track record of natural products in drug and antibioticdiscovery, they have largely been abandoned by the pharmaceuticalsector in favor of large libraries of synthetic molecules.

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