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Chapter 14 : Biosynthesis of Other Classes of Antibiotics

Author: Christopher Walsh
Content Type: Monograph
Publication Year: 2003

Category: Bacterial Pathogenesis

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Biosynthesis of Other Classes of Antibiotics, Page 1 of 2

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Abstract:

This chapter discusses the enzymatic logic for the formation of certain classes of natural products that have been used in human medicine as antibiotics. The aminoglycoside, or aminocyclitol, antibiotics represent products of secondary carbohydrate metabolism and are prevalent among actinomycetes. Starting with the isolation of streptomycin in 1944, various family members were discovered over the following 25 years, including tobramycin in 1970. Novel aminocyclitols continued to be reported into the 1990s. Two main categories of these carbohydrate antibiotics are exemplified by the streptomycin class and by the 2-deoxystreptamine-containing antibiotics that include neomycins, kanamycins, and gentamicins. The glycoside-to-cyclitol conversion, central to streptomycin antibiotic biosynthetic pathway logic, is found in primary metabolism for the generation of inositol-phosphate from glucose-6- phosphate (glucose-6-P) on the way to phosphoinositide membrane lipid biosynthesis. The prospects for combinatorial biosynthesis to make new aminocyclitols, e.g., with more rings and new connectivities, may be good, setting up the systems for new rounds of semisynthetic alkylations and acylations, although it remains to be seen if useful new activities will result. The bicyclic aminocoumarin ring is constructed from tyrosine, in turn derived from chorismate, the key intermediate in aromatic amino acid biosynthesis. Some of the logic and mechanism of nonribosomal peptide synthetase selection, activation, and modification of amino acid monomers is utilized in these amino acid-based antibiotics.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Biosynthesis of Other Classes of Antibiotics
Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Diversely synthesized antibiotics.

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Diversely synthesized antibiotics.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.1

Representative C-P-containing natural products: Bialaphos, aminoethylphosphonate, and fosfomycin.

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Figure 14.1

Representative C-P-containing natural products: Bialaphos, aminoethylphosphonate, and fosfomycin.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.2

Biosynthetic pathway from PEP to fosfomycin.

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Figure 14.2

Biosynthetic pathway from PEP to fosfomycin.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.3

Sequential tandem phosphorylation of the phosphonate moiety in fosfomycin as a self-protection mechanism in .

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Figure 14.3

Sequential tandem phosphorylation of the phosphonate moiety in fosfomycin as a self-protection mechanism in .

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.4

Two major structural classes of aminoglycoside (aminocyclitol) antibiotics: streptomycin and 2′-deoxystreptamine-containing examples kanamycin and gentamicin A.

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Figure 14.4

Two major structural classes of aminoglycoside (aminocyclitol) antibiotics: streptomycin and 2′-deoxystreptamine-containing examples kanamycin and gentamicin A.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.5

Biosynthetic pathway to dihydrostreptomycin-6-P. (A) Upper line: the streptidine-6-P branch; middle line: the TDP-dihydrostreptose branch; bottom line: the NDP-methyl-l-glucosamine branch; (B) glycosyltransferase action to produce dihydrostreptomycin-6-P.

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Figure 14.5

Biosynthetic pathway to dihydrostreptomycin-6-P. (A) Upper line: the streptidine-6-P branch; middle line: the TDP-dihydrostreptose branch; bottom line: the NDP-methyl-l-glucosamine branch; (B) glycosyltransferase action to produce dihydrostreptomycin-6-P.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.6

Export and activation of dihydrostreptomycin-6-P: conversion of the dihydro CHOH to the CHO in streptomycin and extracellular enzymatic dephosphorylation.

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Figure 14.6

Export and activation of dihydrostreptomycin-6-P: conversion of the dihydro CHOH to the CHO in streptomycin and extracellular enzymatic dephosphorylation.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.7

A cluster of 22 genes in eight operons for streptomycin biosynthesis.

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Figure 14.7

A cluster of 22 genes in eight operons for streptomycin biosynthesis.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.8a

Aminocoumarin antibiotics and biosynthetic logic: (A) chlorobiocin, novobiocin, and coumermycin A1 structures; (B) genes for novobiocin pathway; (C) outline of major steps in novobiocin assembly.

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Figure 14.8a

Aminocoumarin antibiotics and biosynthetic logic: (A) chlorobiocin, novobiocin, and coumermycin A1 structures; (B) genes for novobiocin pathway; (C) outline of major steps in novobiocin assembly.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.8b

Aminocoumarin antibiotics and biosynthetic logic: (A) chlorobiocin, novobiocin, and coumermycin A1 structures; (B) genes for novobiocin pathway; (C) outline of major steps in novobiocin assembly.

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Figure 14.8b

Aminocoumarin antibiotics and biosynthetic logic: (A) chlorobiocin, novobiocin, and coumermycin A1 structures; (B) genes for novobiocin pathway; (C) outline of major steps in novobiocin assembly.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.9

Oxidation of aminoacyl--PCPs as a sequestered pool for antibiotic biosynthesis: (A) tyrosine hydroxylation for novobiocin and vancomycin; (B) proline oxidation for coumermycin and undecylprodigiosin; (C) -aminophenylalanine for chloramphenicol.

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Figure 14.9

Oxidation of aminoacyl--PCPs as a sequestered pool for antibiotic biosynthesis: (A) tyrosine hydroxylation for novobiocin and vancomycin; (B) proline oxidation for coumermycin and undecylprodigiosin; (C) -aminophenylalanine for chloramphenicol.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.10

Biosynthetic strategy for chloramphenicol: (A) structure of chloramphenicol; (B) chorismate to -aminophenylalanine; (C) -hydroxylation and carboxyl reduction; (D) dichloroacetylation and N-oxidation.

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Figure 14.10

Biosynthetic strategy for chloramphenicol: (A) structure of chloramphenicol; (B) chorismate to -aminophenylalanine; (C) -hydroxylation and carboxyl reduction; (D) dichloroacetylation and N-oxidation.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.11

Nisin biosynthetic gene cluster.

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Figure 14.11

Nisin biosynthetic gene cluster.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.12

Enzymatic modification of prepro form of the lantibiotic nisin: (A) dehydration of Ser and Thr side chains by NisB; (B) thioether formation by attack of Cys side chains catalyzed by NisC; (C) proteolytic cleavage of the N-terminal 23-residue leader sequence by NisP.

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Figure 14.12

Enzymatic modification of prepro form of the lantibiotic nisin: (A) dehydration of Ser and Thr side chains by NisB; (B) thioether formation by attack of Cys side chains catalyzed by NisC; (C) proteolytic cleavage of the N-terminal 23-residue leader sequence by NisP.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.13

Genes for microcin B17 production and enzymatic maturation to the active antibiotic.

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Figure 14.13

Genes for microcin B17 production and enzymatic maturation to the active antibiotic.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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Figure 14.14

Enzymatic maturation of prepro microcin B17: (A) thiazole and oxazole ring formation catalyzed by McbB McbC, and McbD; (B) proteolytic removal of the N-terminal 26-residue propeptide.

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Figure 14.14

Enzymatic maturation of prepro microcin B17: (A) thiazole and oxazole ring formation catalyzed by McbB McbC, and McbD; (B) proteolytic removal of the N-terminal 26-residue propeptide.

Citation: Walsh C. 2003. Biosynthesis of Other Classes of Antibiotics, p 220-234. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch14
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