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Chapter 19 : Prospects for New Molecules and New Targets

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Prospects for New Molecules and New Targets, Page 1 of 2

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Abstract:

Finally, we turn to lessons and opportunities for next-generation antibiotics, based on detection of newly active scaffolds, the search for new molecular structures, and how such discoveries can be enabled by smart assays.

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Figures

Image of Figure 19.0
Figure 19.0

Kibdelomycin, a novel DNA gyrase inhibitor natural product, bound to the ParE topoisomerase (topo) IV subunit. (Image prepared using PyMOL from PDB file 4URL [Lu et al., 2014].)

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Figure 19.1
Figure 19.1

Recent total synthetic routes to the tetracycline nucleus have revolutionized the number of analogs available and the substituents accessible on the A ring. Eravacycline is in late-stage clinical trials (Wright et al., 2014; Grossman et al., 2015).

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Figure 19.2
Figure 19.2

A second-generation oxazolidinone, tedizolid phosphate, was recently approved, and another linezolid analog, radezolid, is in clinical trials.

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Figure 19.3
Figure 19.3

(a) Boger and colleagues achieved the total synthesis of the amidino aglycone of vancomycin to combat vancomycin-resistant enterococci and then used the two pathway glycosyltransferases to complete chemoenzymatic synthesis of the amidino vancomycin analog. (b) Dalbavancin, a second-generation teicoplanin, was approved in 2014. (c) Plazomicin, a semisynthetic analog of sisomicin, is in late-stage clinical trials.

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Figure 19.4
Figure 19.4

Three recent antibiotic scaffolds available for further elaboration: platensimycin, abyssomicin, and pleuromutilin.

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Figure 19.5
Figure 19.5

New antibiotics that target the GyrB subunit of DNA gyrase. (a) Kibdelomycin was recently discovered in a smart screen. (b) Cystobactamids were detected by activity screening of myxobacteria. Albicidin had been known for decades, but its structure has only recently been determined and it is clearly an analog of the cystobactamids. (c) The Trius synthetic pyrrolopyrimidine also inhibits GyrB.

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Figure 19.6
Figure 19.6

Antisense knockdown strategy in a 245-gene library of identified the gene, encoding glucosamine synthase in MRSA strains showing β-lactam resistance. (Reprinted from Lee et al. [2011b] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Figure 19.7
Figure 19.7

The power of combinations is demonstrated by finding that an inhibitor of the lipid II flippase synergizes with carbapenem antibiotics.

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Vignette 19.1
Vignette 19.1

Teixobactin, a novel nonribosomal peptidolactone from a previously unculturable bacterium, targets lipid II.

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Figure 19.8
Figure 19.8

Two molecular scaffolds that potently inhibit bacterial thymidylate kinase.

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Figure 19.9
Figure 19.9

NAD ligase, a repair catalyst for broken strands in DNA. (a) Schematic for adenylation of the active-site Lys-NH of LigA, followed by attack of the 5′-P end of the break to yield an activated ADP end subject to capture by the 3′-OH across the break to effect strand repair. (b) Nanomolar inhibitor of the NAD-dependent DNA ligase of Gram-negative and Gram-positive bacteria.

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Figure 19.10
Figure 19.10

Bacterial cyclic di-GMP synthase catalyzes the cyclic diphosphodiester signaling molecule from two molecules of GTP.

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Figure 19.11
Figure 19.11

Gemmacin B and emmacin as core scaffolds for diversification.

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Figure 19.12
Figure 19.12

First-generation efforts to alter the framework of the 14-membered macrolide deoxyerythromycin B by single module deletion or catalytic swapping allowed systematic alteration of the macrocyclic scaffold. (Adapted from McDaniel et al. [1999].)

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Figure 19.13
Figure 19.13

Structures of lactocillin and LFF571. Lactocillin is a novel thiazolyl peptide macrocycle isolated after genomic sequence analysis of a human vaginal .

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Figure 19.14
Figure 19.14

Clinically useful combinations of antibiotic pairs: amoxicillin and clavulanate constitute Augmentin; piperacillin and tazobactam are the active components of Zosyn; a fixed-dose combination of sulfamethoxazole and trimethoprim are found in cotrimoxazole; and rifampin and isoniazid are given concurrently as first-line agents for the treatment of tuberculosis.

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Vignette 19.2
Vignette 19.2

Sultamicillin and thiomarinol A release two active fragments on metabolic processing.

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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Image of Vignette 19.3
Vignette 19.3

Phage-mediated delivery of CRISPR-associated RNA-guided nuclease to cut and destroy a bacterial target gene.

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19
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References

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Tables

Generic image for table
Table 19.1

The natural tripeptide dapdiamide C restores β-lactam sensitivity to MRSA strains, as does the wall teichoic acid inhibitor tunicamycin

Citation: Walsh C, Wencewicz T. 2016. Prospects for New Molecules and New Targets, p 398-419. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch19

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