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Chapter 16 : New Molecules

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Abstract:

This chapter talks about synthetic compound libraries and the new approaches with natural products as antibiotic candidates. It summarizes some recent efforts on reprogramming of biosynthetic assembly lines of polyketides (PKs) and nonribosomal peptides (NRPs) assembly lines and of the post-assembly-line enzymatic tailoring reactions to create new variants of natural products, “unnatural natural products." Carrying out combinatorial reprogramming on a large scale requires large numbers of polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) gene clusters, an understanding of the rules for cutting and pasting to maximize autonomously folding modules, and rapid methods for gene shuffling. Some of the most intriguing natural products have five-ring sulfur and oxygen heterocycles, thiazoles, and oxazoles, which arise from cyclization of cysteinyl-SH and seryl-OH side chains on the preceding peptide bond carbonyl, catalyzed by cyclization (Cy) domains that are variants of the peptide bond-forming condensation domains. Reconstitution of PKS-NRPS and NRPS-PKS interfaces has been achieved with purified components in vitro to establish the recognition patterns of the KS, C, and Cy catalytic, chain-elongation domains, as a prelude to combinatorial strategies that would make novel hybrid PK-NRP-PK structures.

Citation: Walsh C. 2003. New Molecules, p 270-282. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch16

Key Concept Ranking

Antibacterial Agents
0.50668097
Cyclic Amino Acids
0.44223648
0.50668097
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Figures

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Untitled

A library of erythronolide macrolide variants by reprogramming the DEBS synthase domains. (From McDaniel et al. [1999], with permission.)

Citation: Walsh C. 2003. New Molecules, p 270-282. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch16
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Figure 16.1

Examples of approaches to templated libraries: (A) tetracyclic templated libraries; (B) macrocyclic templated libraries. (From Arya et al. [2001], with permission.)

Citation: Walsh C. 2003. New Molecules, p 270-282. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch16
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Image of Figure 16.2
Figure 16.2

Changes that have been engineered in the 6-DEB macrolide scaffold. (From Strohl [2001], with permission.)

Citation: Walsh C. 2003. New Molecules, p 270-282. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch16
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Figure 16.3

Routes to altered macrolactone ring size in the DEBS assembly line.

Citation: Walsh C. 2003. New Molecules, p 270-282. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch16
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Figure 16.4

Manipulation of the TDP-deoxyhexose pathways in : (A) lack of desosamine moiety when the 3-position remains as a ketone in pikromycin; (B) replacement of by to alter the sugars on the macrolide scaffold.

Citation: Walsh C. 2003. New Molecules, p 270-282. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch16
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Image of Figure 16.5
Figure 16.5

Four-enzyme cassettes for de novo generation of the 4-OH-PheGly and 3,5- (OH)2-PheGly monomers for vancomycin and teicoplanin biosynthesis.

Citation: Walsh C. 2003. New Molecules, p 270-282. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch16
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Image of Figure 16.6
Figure 16.6

Tailoring enzymes embedded in in NRPS Assembly Lines: (A) -methyltransferases; (B) cyclization domains to make oxazoline and thiazoline rings.

Citation: Walsh C. 2003. New Molecules, p 270-282. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch16
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Figure 16.7

NRP-PK hybrid molecules: bleomycin A2, epothilone D, and pristinamycin IIA.

Citation: Walsh C. 2003. New Molecules, p 270-282. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch16
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Figure 16.8

Pristinamycin IIA is a product of a putative hybrid assembly line of NRPS-PKSNRPS- PKS modules.

Citation: Walsh C. 2003. New Molecules, p 270-282. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch16
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Image of Figure 16.9
Figure 16.9

Enzymatic biosynthesis of hybrid glycopeptides in the teicoplanin and vancomycin class by combinations of TDP-sugars and glycosyltransferase swaps.

Citation: Walsh C. 2003. New Molecules, p 270-282. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch16
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