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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

GPAs: a structurally diverse class of bacteriallyproduced antibiotics.
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fig3: GPAs: a structurally diverse class of bacteriallyproduced antibiotics.

Mentions: Glycopeptide antibiotics (GPAs) offer a useful examplewhere weand others have initiated efforts to explore the applicability ofsynthetic biology approaches in an effort to expand the chemical diversityof a natural product class. GPAs (Figure 3)are critically important antibiotics that target Gram-positive bacteriaby binding to the acyl-d-alanyl-d-alanine terminusof growing peptidoglycan. This interaction physically blocks cellwall biosynthetic enzymes, inhibiting cell growth and division. Theyremain essential drugs for the treatment of life-threatening infectionscaused by important human pathogens such as Staphylococcusaureus and Enterococcus sp. The antibioticsconsist of a heptapeptide scaffold that is matured to the active antibioticvia a series of tailoring enzymes that oxidatively catalyze 3–4intramolecular cyclizations and a variety of modifications includingglycosylation, halogenation, acylation, etc. (Figure 4). Two distinct peptide scaffolds that include two unusualamino acids, 4-hydroxylphenylglycine (Hpg) and 3,5-dihydroxyphenylglycine(Dpg), are in current clinical use exemplified by vancomycin (Leu-Bht-Asn-Hpg-Hpg-Bht-Dpg)and teicoplanin (Hpg-Tyr-Dpg-Hpg-Hpg-Bht-Dpg). Since the discoveryof vancomycin in 1953, a large number of GPAs have been isolated.These molecules generally retain the canonical heptapeptide coresand vary in their accessorization by various functional groups. Nicolaouand colleagues have catalogued an exhaustive list of all of the functionalgroups attached at various positions in different GPAs.31 The first reported GPA biosynthetic gene clustersrevealed a predicted set of nonribosomal peptide synthetase unitsrequired for assembling the peptide scaffold along with genes encodingamino acid and sugar biosynthesis, self-resistance, export, and tailoringenzymes.32,33 This pattern is repeated in all other GPAclusters (Figure 5). Here we will focus onthe molecules with known biosynthetic machinery, which can be utilizedto assemble novel GPAs using a synthetic biology approach. These includethe A47934, A40926, teicoplanin, chloroeremomycin, vancomycin, balhimycin,VEG, TEG, CA37, CA878, and CA915 GPA biosynthetic clusters along withsome information from our unpublished work on UK68597, ristocetin,and the new GPA pekiskomycin.


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

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

GPAs: a structurally diverse class of bacteriallyproduced antibiotics.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: GPAs: a structurally diverse class of bacteriallyproduced antibiotics.
Mentions: Glycopeptide antibiotics (GPAs) offer a useful examplewhere weand others have initiated efforts to explore the applicability ofsynthetic biology approaches in an effort to expand the chemical diversityof a natural product class. GPAs (Figure 3)are critically important antibiotics that target Gram-positive bacteriaby binding to the acyl-d-alanyl-d-alanine terminusof growing peptidoglycan. This interaction physically blocks cellwall biosynthetic enzymes, inhibiting cell growth and division. Theyremain essential drugs for the treatment of life-threatening infectionscaused by important human pathogens such as Staphylococcusaureus and Enterococcus sp. The antibioticsconsist of a heptapeptide scaffold that is matured to the active antibioticvia a series of tailoring enzymes that oxidatively catalyze 3–4intramolecular cyclizations and a variety of modifications includingglycosylation, halogenation, acylation, etc. (Figure 4). Two distinct peptide scaffolds that include two unusualamino acids, 4-hydroxylphenylglycine (Hpg) and 3,5-dihydroxyphenylglycine(Dpg), are in current clinical use exemplified by vancomycin (Leu-Bht-Asn-Hpg-Hpg-Bht-Dpg)and teicoplanin (Hpg-Tyr-Dpg-Hpg-Hpg-Bht-Dpg). Since the discoveryof vancomycin in 1953, a large number of GPAs have been isolated.These molecules generally retain the canonical heptapeptide coresand vary in their accessorization by various functional groups. Nicolaouand colleagues have catalogued an exhaustive list of all of the functionalgroups attached at various positions in different GPAs.31 The first reported GPA biosynthetic gene clustersrevealed a predicted set of nonribosomal peptide synthetase unitsrequired for assembling the peptide scaffold along with genes encodingamino acid and sugar biosynthesis, self-resistance, export, and tailoringenzymes.32,33 This pattern is repeated in all other GPAclusters (Figure 5). Here we will focus onthe molecules with known biosynthetic machinery, which can be utilizedto assemble novel GPAs using a synthetic biology approach. These includethe A47934, A40926, teicoplanin, chloroeremomycin, vancomycin, balhimycin,VEG, TEG, CA37, CA878, and CA915 GPA biosynthetic clusters along withsome information from our unpublished work on UK68597, ristocetin,and the new GPA pekiskomycin.

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