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Chapter 18 : Underexploited Pathways and Targets for Antibiotics

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Underexploited Pathways and Targets for Antibiotics, Page 1 of 2

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Abstract:

While the antibiotics with broad-spectrum activity in human clinical infections act on only a small set of targets, described in detail in chapters 4 to 8, we have also noted some narrow-spectrum antibiotics that work clinically against particular pathogens. Historically, the suite of first-line antibiotics for treatment of tuberculosis—isoniazid, rifampin, pyrazinamide, and ethambutol—are such therapeutic agents (chapter 13); they are not used in other antimicrobial contexts.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Figures

Image of Figure 18.0
Figure 18.0

LpxC acetylenic inhibitors CHIR-090 and LPC-009. The LpxC–CHIR-090 complex is shown on the left. (Reprinted from Barb et al. [2007a] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.1
Figure 18.1

Acetyl-CoA carboxylase (AccABCD) provides the malonyl-CoA needed for chain elongation cycles in fatty acid synthesis and is the target for andrimide, moiramide, and pyridopyrimidine inhibitors. FabF and FabI in the fatty acid synthesis metabolic cycle are targets of platencin and platensimycin and of isoniazid and triclosan, respectively, as elaborated in subsequent figures.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.2
Figure 18.2

Activation of the prodrug isoniazid by KatG and oxygen leads to a reactive intermediate that forms an adduct with NAD. This adduct has a high affinity for the active site of the FabI enoyl reductase and blocks fatty acid biosynthesis.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.3
Figure 18.3

Both platencin and platensimycin, whose biosynthesis is depicted in chapter 16, are inactivators of the FAS enoyl reductase by covalent capture of the active-site thiol addition to the enone moiety. Shown on the right are the conformers from cocrystal structures with mutant forms of bacterial FabF target proteins lacking the nucleophilic cysteine. (Three-dimensional images created from PDB files 3HO2 [platencin] and 2GFX [platensimycin] from PyMOL.)

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.4
Figure 18.4

Triclosan, the pyridone PT-166, and AFN-1252 are slow, tight-binding inhibitors of FabI enoyl reductases.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.5
Figure 18.5

The two half reactions of acetyl-CoA carboxylase, depicting both carboxyphosphate and -carboxybiotin intermediates. (a) The carboxyphosphate-forming step to activate bicarbonate for capture by the tethered biotin (b). (c) The carboxyl transfer reaction in this example involves capture by the thioester enolate of acetyl-CoA. Both the lipopeptide andrimid and a synthetic pyridopyrimidine are potent inhibitors of this carboxyltransferase subunit of bacterial acetyl-CoA carboxylases.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.6
Figure 18.6

(a) Classical and (b) nonclassical pathways to the isoprenyl diphosphate isomers. Fosmidomycin, a phosphonate antimetabolite, blocks the first enzyme in the nonmevalonate pathway to isoprenyl diphosphates.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.7
Figure 18.7

Schematic of a lipopolysaccharide molecule from a Gram-negative bacterium.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.8
Figure 18.8

Schematic of the LpxA, -C, and -D reactions in the lipid A biosynthetic pathway. (Reprinted from Walsh and Wencewicz [2014] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.9
Figure 18.9

Structure-guided efforts inspired by the prototype alkynyl hydroxamate LpxC inhibitor CHIR-090 revealed the next-generation diacetylenic inhibitor LPC-009, which overcomes point mutations (G214 to S214 in ) associated with CHIR-090 resistance in Gram-negative pathogens. (Images created using PyMOL from PDB entries 2JT2 [LpxC–CHIR-090 complex] and 3P3C [LpxC–LPC-009 complex].) For both cases, the structure was solved for wild-type LpxC from complexed to the inhibitor and a point mutation of G198 to S198 was inserted computationally into the PyMOL structure to demonstrate in this figure how this mutation leads to steric repulsion in the LpxC–CHIR-090 complex. (Reprinted from Walsh and Wencewicz [2014] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.10
Figure 18.10

(a) Schematic of the transport and insertion of LPS into the outer leaflet of the outer membrane of Gram-negative bacteria by LptABCDEFG. (Reprinted from Zhang et al. [2009] with permission.) (b) The LptG β-barrel protein is the target for the naturally occurring defensin plectasin and for a synthetic peptidomimetic, POL7001, based on the protegrin structure with disulfide bridge replacement by a pair of prolines to give a cyclic scaffold.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.11
Figure 18.11

Schematic of the multiprotein machinery assembled at the divisome. The elongasome complex is recruited by MreB and inserts PG units in elongation. The divisome assembly is directed by the GTPase FtsZ. (Panels a, b, and c from T. den Blaauwen and panel d from Alessandro Senes, used with permission.)

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.12
Figure 18.12

Structures of PC190723, a selective first-generation FtsZ inhibitor, and an improved difluorobenzamide scaffold formulated as a succinyl ester prodrug.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.13
Figure 18.13

Schematic of the thiamin diphosphate riboswitch. Pyrithiamin diphosphate is an inhibitory ligand. (Image from Chris Abell, used with permission.)

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.14
Figure 18.14

Structure of riboswitch with FMN (red) bound (PDB file 3F4H [Serganov, 2009]). The flavin analog roseoflavin is a competitive ligand.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.15
Figure 18.15

Actinonin, a naturally occurring inhibitor of bacterial peptidyl deformylase by metal chelation, has served as a starting point for synthetic hydroxamates and reverse hydroxamates such as GSK1322322.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.16
Figure 18.16

(a) Bacterial protein synthesis starts with -formyl-Met-tRNA, which is removed cotranslationally. (b) Peptide deformylase is specific for removal of the N-terminal formyl group via an Fe(II)-based mechanism.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.17
Figure 18.17

(a) Schematic for processing of protein substrates for degradation by chambered bacterial proteases of the Clp family. Proteins for degradation have to be unfolded and threaded into the chambers where the protease active sites are displayed. (b) Several of the Clp family proteases are shown, along with the Lon and FtsH chambered proteases with a list of associated adapter proteins. (Reprinted from Kirstein et al. [2009] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.18
Figure 18.18

ADEP binding to intersubunit allosteric sites activates the Clp machine by widening the pore for disregulated passage of proteins into the protease chambers. (Image created using PyMOL from PDB entry 3MT6 [Li et al., 2010].)

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.19
Figure 18.19

(a) Signal peptidases cleave the signal sequences from proteins passing into or through bacterial inner membranes. (b) Arylomycin, actinocarbasin, and the biphenyl analog of actinocarbasin are signal peptidase inhibitors.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.20
Figure 18.20

Type I to V bacterial secretion systems. (Reprinted from Fronzes et al. [2009] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.21
Figure 18.21

Virstatin has an unknown target in the blockade of chlorotoxin, while guadinomine A and aurodox are inhibitors of type III secretion systems.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.22
Figure 18.22

(a) Biosynthesis of -acylhomoserine lactone quorum sensors; (b) inhibition of action of the 3-keto-dodecanoylhomoserine lactone by triazolyl inhibitors; (c) quinolone quorum sensor for pseudomonads; (d) peptidylthiolactone quorum sensor for streptococci.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.23
Figure 18.23

(a) Structure of virulence factor staphyloxanthin; (b) biosynthetic pathway to dehydrosqualene intermediate and blockade by the inhibitor BPH-652.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.24
Figure 18.24

Siderophores contain three types of functional groups to coordinate ferric iron. (a) Enterobactin, with three catechol ligands. (b) Mycobactin J, with both oxazoline and hydroxamate ligands. (c) Aerobactin, a classic hydroxamate siderophore of enterococci.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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Image of Figure 18.25
Figure 18.25

Aminoacyl sulfonamides are stable analogs of aminoacyl-AMP intermediates in siderophore NRPS assembly lines.

Citation: Walsh C, Wencewicz T. 2016. Underexploited Pathways and Targets for Antibiotics, p 366-397. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch18
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