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Chapter 15 : New Looks at Targets

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Abstract:

From a field of research and inquiry that was effectively target poor for the past three decades, there is now at least a temporary embarrassment of target riches, with dozens to hundreds of gene products that are candidates as novel targets. The identification of 150 genes essential for viability in the important pathogen Staphylococcus aureus has been undertaken systematically by expression of antisense ΔRNA to ablate gene function. Some prospects in the traditional validated target areas of cell wall biosynthesis, protein biosynthesis, and DNA replication and repair with certain inhibitors will first have to be noted, followed by pointing out some less traditional targets that command new attention. In addition to the targets that are and will be emerging from the genomics approaches noted at the beginning of this chapter, there are some other enzymes and processes for which there is already reasonable to strong justification for study as novel antibacterial targets. Pyrophosphorylation at the primary alcohol and phosphorylation at the tertiary alcohol by two kinases set up the olefin-forming decarboxylation/Pi elimination reaction to yield the allylic isomer dimethyallyl-pyrophosphate (dimethylallyl-PP) (3). Finally, the isopentenyl-PP isomerase moves the double bond to the (2 isomer, isopentenyl-PP, so both isomers are available for elongation reactions.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Untitled

Time line for introduction of new classes of antibiotics into clinical practice.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.1

Example of a genomics-based approach to new targets for antibacterial drugs in respiratory tract infections. (From Rosamond and Allsop [2000], with permission.)

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.2

Genomics approaches to antimicrobial drugs. (From Rosamond and Allsop [2000], with permission.)

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.3

Action of sortase to covalently tether outer membrane proteins to the pentaglycine extenders on S. aureus peptidoglycan strands: (A) the pentaglycine-containing PG strands; (B) cleavage of LPXTG sequence in precursor protein substrates and transpeptidation by sortase. (From Mazmanian et al. [2001], with permission.)

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Image of Figure 15.4
Figure 15.4

Action of the M. tuberculosis mycolyltransferase Ag85: (A) trehalose dimycolate; (B) the mycolyl transfer reaction.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.5

Defined lipid II substrate analogs for membrane transglycosylase assay.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.6

Chlorobiphenyl analogs of chloroeremomycin and vancomycin active against VRE: (A) specific compounds; (B) aryl glycopeptides active against VRE with the D-Ala-D-Ala binding site destroyed.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.7

Structures of pleuromutilin family members that block the peptidyltransferase center on the ribosome.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.8

Everninomycin structure.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.9

Binding site of everninomycin on 23S rRNA. (From Mazmanian et al. [2001], with permission.)

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.10

Examples of the thiopeptide class of antibiotics containing thiazole and oxazole rings.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.11

Binding site for thiopeptide GE2270A on the elongation factor EF-Tu. (From Heffron and Jurnak [2000], with permission.)

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.12

Synthetic dimers of neamine derivatives as RNA-targeting aminoglycoside mimetics.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.13

Action of peptide deformylase and methionine aminopeptidase to trim away fMet residues at the N termini of bacterial proteins.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.14

The natural product actinonin is a metal-chelating inhibitor of peptide deformylase.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Image of Figure 15.15
Figure 15.15

Mupirocin: an inhibitor of Ile-tRNA synthetase.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Image of Figure 15.16
Figure 15.16

Figure 15.16 Naturally occurring aminocoumarin inhibitors of DNA gyrase.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Image of Figure 15.17
Figure 15.17

Binding of novobiocin to the ATP site on the GyrB subunit with selected key interactions displayed. (From Lewis et al. [1996], with permission.)

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Image of Figure 15.18
Figure 15.18

(A) The peptide macrolactone cyclothialidine is a DNA gyrase inhibitor; (B) proposed route for cyclization of a linear nonribosomal pentapeptide precursor.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Image of Figure 15.19
Figure 15.19

Structure of the natural product cerulenin: an alkylating inactivator of fatty acid synthases.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Image of Figure 15.20
Figure 15.20

(A) Triclosan, an antibacterial antiseptic, inhibits enoyl-ACP reductase. (B) The antitubercular drug isoniazid requires metabolic oxidation to generate an acylated NAD in the active site of the target enoylreductase.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Image of Figure 15.21
Figure 15.21

Reaction catalyzed by phosphopantetheinyltransferase in priming of apo ACP domains.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Image of Figure 15.22
Figure 15.22

Comparison of the (A) nonclassical and (B) classical pathways for isoprenoid biosynthesis in bacteria: new enzyme targets.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.23

Divergence of prenyltransferase pathways between cis- and trans-prenyl transfers.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Image of Figure 15.24
Figure 15.24

The glyoxylate shunt and the role of isocitrate lyase.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Image of Figure 15.25
Figure 15.25

(A) Structure of the lipid A core; (B) deacetylation of UDP-GlcNAc by LpxC; (C) phenyl-oxazolyl hydroxamate inhibitors of the zinc enzyme LpxC. M2+ is the enzyme-bound metal cation required for catalysis.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Figure 15.26

Two-component sensor/response regulator logic.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Image of Figure 15.27
Figure 15.27

The autoinducing peptide locus, the agr operon, of S. aureus.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Image of Figure 15.28
Figure 15.28

(A) The proposed reaction mechanism for acylhomoserine lactone (AHL) synthases. (B) Enzymatic generation of the AHL quorum signals.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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Image of Figure 15.29
Figure 15.29

Inhibitors reported for efflux pumps.

Citation: Walsh C. 2003. New Looks at Targets, p 236-269. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch15
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