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Chapter 7 : Antibiotics That Target DNA and RNA Information Transfer

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Antibiotics That Target DNA and RNA Information Transfer, Page 1 of 2

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Abstract:

In the initial version of the central dogma of biology, macromolecular information flow is from DNA to RNA to proteins. Information flows from the master repository of genetic information in long-lived DNA to the transcribed mRNAs, which, with short half-lives, carry instructions encoded in particular genes to the proteins, translated from mRNAs in protein synthesis, that carry out the nucleic acid-encoded instructions. Chapter 6 detailed the many natural products that are clinically useful classes of antibiotics that target one or more steps in protein biosynthesis, based on the distinctions in aminoacyl-tRNA synthetases and in the small and large subunits of the ribosome that have evolved between prokaryotes and eukaryotes. We have seen that most of those antibiotics target rRNA regions.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Figures

Image of Figure 7.0
Figure 7.0

RNA polymerase inhibitors: room for new molecules? (Reprinted from Walsh and Wencewicz [2014] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.1
Figure 7.1

Selected antitumor agents. These molecules prevent DNA replication by binding to molecules of DNA and preventing enzymes from binding and performing their proper functions.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.2
Figure 7.2

Structures of chloroquine and nalidixic acid. Nalidixic acid is an impurity isolated during the synthesis of chloroquine that was shown to have antibiotic properties. It is considered to be the first of the quinolones.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.3
Figure 7.3

Second generation (a) and third generation (b) fluoroquinolones and fluoroquinolones currently in development (c). Each generation introduced different modifications (shown in red) to the original fluoroquinolone scaffold (shown in black) designed to improve efficacy.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.4
Figure 7.4

Supercoiling of DNA around replication fork. (a) Normal DNA in the relaxed state shows no supercoiling. During replication, DNA helicase binds to the double-stranded molecule and begins to unwind it from the middle (b). As this process continues, the strands on either side of the fork become either looser or tighter (c), leading to supercoiling of the DNA. To alleviate tension from supercoiling, DNA gyrase cuts through both strands of the DNA and reseals them on the opposite side. This returns the DNA to its previous relaxed state (d). When DNA gyrase is inhibited, DNA has no way to relieve the extra tension from supercoiling. After some time in the supercoiled state, the buildup of mechanical stress will cause the DNA to “break,” ultimately leading to cell death (e).

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.5
Figure 7.5

After replication, daughter chromosomes are linked together (a). DNA gyrase breaks one of the chromosomes (b) and then positions the cut site outside of the second chromosome (c). After resealing the cut, the enzyme falls off and two separated chromosomes are left (d).

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.6
Figure 7.6

Mechanism of DNA gyrase. In step 1, gyrase binds to the DNA in an initial enzyme-substrate complex. The two subunits then each break one of the strands of the dsDNA by attacking the backbones with hydroxyl groups located on tyrosine residues (Tyr122). This results in both strands of DNA being covalently bound to the enzyme through phosphodiester bonds on their 5′ ends (2). This step is shown in detail in the inset at the top of the figure. In step 3, the enzyme pulls the DNA through the cut site to effect topological relaxation. Once this occurs, DNA gyrase reseals the two strands of DNA (4) and then releases it (5).

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.7
Figure 7.7

Moxifloxacin in the active site of ParC. Two molecules of moxifloxacin are able to bind in the active site of ParC, as there are two similar cut regions. The molecule fits nicely in between the DNA base pairs, and π-stacking between the aromatic rings encourages inhibition. Two of the moxifloxacin oxygens bind to the active-site magnesium ion, further establishing its potency as an inhibitor. Red spheres represent water molecules.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.8
Figure 7.8

Quinazolinedione scaffolds. Panel a shows the basic structure of the scaffold, and panel b shows two examples based on this scaffold. On the left is nitraquazone, and on the right is a synthetic analog developed for increased potency.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.9
Figure 7.9

Structures of novobiocin, clorobiocin, and dimeric coumermycin, which target the GyrB subunit of DNA gyrase.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.10
Figure 7.10

Cyclothialidine is a natural product inhibitor of DNA gyrase that imparts its inhibitory effects by binding at the β subunit. While cyclothialidine displays poor whole-cell antibacterial activity, synthetic variants have been made that display improved whole-cell antibacterial activity and excellent ability to clear infections in a mouse model.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.11
Figure 7.11

Quinazoline 2,4- and 3,5-diones are synthetic structures inspired by the fluoroquinolone scaffold that show inhibitory activity against FQ-resistant pathogens.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.12
Figure 7.12

Structure of prokaryotic RNAP. The β and β′ subunits are red and pink, respectively, and the two identical α subunits are shown in dark and light gray. The ω subunit is shown in white. The σ subunit is not shown in this figure, but attaches to the enzyme after the binding of DNA.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.13
Figure 7.13

Rifamycin SV, the first of the rifamycin analogs to enter the clinic. Rifampin (rifampicin), rifapentine, and rifabutin are all derivatives of the original rifamycin scaffold with the additional substituents shown in red.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.14
Figure 7.14

(a) Rifampin binds slightly upstream of the active site in RNA polymerase, which results in the truncation of transcribed RNA. This leads to an inability to translate the genetic material into proteins, which ultimately leads to cell death. (b) The binding of rifampin in the RNA exit tunnel is strengthened by hydrogen bonds between oxygens of the antibiotic and hydrogens of several amino acid residues in RNAP. Amino acid numbering is from RNA polymerase (Campbell et al., 2005).

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.15
Figure 7.15

(a) The structure of sorangicin A. (b) Overlapping conformations of sorangicin (in red) and rifampin (in pink) while in the RNA polymerase binding pocket.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.16
Figure 7.16

The structure of lipiarmycin (fidaxomicin), with the 18-membered macrolactone framework in red.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Figure 7.17
Figure 7.17

Structures of the RNA polymerase inhibitors myxopyronin A/B and related variant corallopyronin and the polyketide ripostatin.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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Image of Vignette 7.1
Vignette 7.1

cells, spore-forming members of the human gut microbiome, can expand in numbers in the GI tract after broad spectrum antibiotic usage. The resultant colitis can be life-threatening and has prompted the recent development and approval of fidaxomicin for this indication. Credit: Janice Carr/CDC/Lois S. Wiggs; CDC-PHIL ID#9999.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Target DNA and RNA Information Transfer, p 148-162. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch7
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