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Chapter 13 : Tuberculosis: A Formidable Challenge for Antibiotic Therapy

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Tuberculosis: A Formidable Challenge for Antibiotic Therapy, Page 1 of 2

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Abstract:

Tuberculosis (TB), also known as the white plague, has been a life-threatening bacterial disease for millennia, with some 2 billion humans currently estimated to harbor the bacterial pathogens in latent form. The causative agent, , may have moved from animal reservoirs to humans when wild animals became domesticated as livestock some 10,000 years ago. As far back as the time of Hippocrates, TB was a notably common malady. Robert Koch in 1882 wrote that one in seven humans died from TB, and for those who died in middle age, it was responsible for a third of mortality. Current estimates of global mortality from TB are about 1.7 million deaths per year, with an incidence of almost 10 million new cases annually (World Health Organization, 2014).

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Figure 13.0
Figure 13.0

“Fight tuberculosis.” (Image from the U.S. National Library of Medicine, used with permission.)

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Figure 13.1
Figure 13.1

Schematic of the complex cell envelope of . External to the typical peptidoglycan layer is a lipoarabinomannan layer and then an arabinogalactan oligosaccharide scaffold that in turn connects covalently to the long-chain mycolic acids, among other acyl lipids and surface proteins.

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Figure 13.2
Figure 13.2

(a) Structure of two of the major α-OH-mycolic acids, bearing two long acyl chains, including cyclopropane rings. (b) Branched hexa-arabinan mycolic ester units, where four of the five arabinose units have mycolic acids in ester linkage to the sugar C hydroxyl groups. This schematic also shows how the mycolyl arabinan motifs connect to the galactofuranan layer, which is in turn tethered through a rhamnosyl-GlcNAc disaccharide linker to the peptidoglycan layer.

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Figure 13.3
Figure 13.3

Progressive development of lung lesions during progression of TB infection.

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Figure 13.4
Figure 13.4

Five antibiotics that comprise the options for front-line combination therapy for tuberculosis treatment: rifampin, isoniazid, ethionamide, pyrazinamide, and ethambutol.

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Figure 13.5
Figure 13.5

Isoniazid, ethionamide, and pyrazinamide are prodrugs. Isoniazid and ethionamide are metabolically activated to generate adducts with cofactor NAD in the active site of the InhA enoyl reductase. The high affinity of the adducts for the active site blocks enzyme activity and deprives of fatty acid synthesis. Hydrolysis of the amide in pyrazinamide to the free acid generates the active form of the antibiotic.

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Figure 13.6
Figure 13.6

Binding pockets of the InhA enoyl reductase of . (a) NADH is shown in red, and the -2-hexadecanoyl--acetyl cysteamine thioester substrate is shown in blue. The two molecules occupy distinct sites within the cavity of the InhA active site. The space occupied by each natural ligand is present in panels b and c as colored dots. (b) The isoniazid-NAD covalent adduct (isoniazid portion of the molecule is shown in blue and NAD portion in red) occupies the NADH binding pocket. (c) Pyridomycin (blue) occupies both the NADH and substrate binding pockets. (d) Chemical structure of the nonribosomal peptide-polyketide hybrid pyridomycin produced by soil streptomycetes. (Images in panels a to c created using PyMOL from superimposed PDB files 1BVR, 2IEB, and 4BII.)

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Figure 13.7
Figure 13.7

There are multiple gene products encoding arabinosyltransferases. Inhibition by ethambutol of arabinan chain elongation compromises the integrity of the cell envelope. The arabinosyl donor is the membrane-bound decaprenyl arabinose.

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Figure 13.8
Figure 13.8

PAS acts as a dead-end substrate in the folate biosynthetic pathway to cause thymineless death. DHPS, dihydropteroate synthase; DHFS, dihydrofolate synthase; DHFR, dihydrofolate reductase.

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Vignette 13.1
Vignette 13.1

The last step in NAD biosynthesis is NadE-mediated amidation to generate the pyridine carboxamide moiety of NAD. It may be a new target for antimycobacterial drug discovery.

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Figure 13.9
Figure 13.9

(a) The nitroimidazole agents PA-824 and OPC-67683 are prodrugs. (b) They undergo metabolism by mycobacterial deazaflavin-dependent oxidoreductases to generate NOX species thought to be the proximal agents that disrupt hemeprotein function. (c) Proposed mechanism for reductive activation of the nitro groups in the prodrug forms.

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Figure 13.10
Figure 13.10

(a) Decaprenyl ribose isomerase generates the arabinose donor for arabinan biosynthesis (see Fig. 13.7 ). (b) Benzothiazones as covalent inactivators of the decaprenyl ribose isomerase. Blockade of conversion of decaprenyl ribose to decaprenyl arabinose blocks supply of the arabinose building blocks for the arabinan layer of the cell envelope. (c) Trifluoromethylquinoxaline carboxylates are noncovalent inhibitors of the isomerase.

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Figure 13.11
Figure 13.11

Oxathiazol-2-ones as latent acylating agents of the active-site threonine 1 of the mycobacterial proteasome. (a) Representative oxathiazol-2-one molecules. (b) Proposed mechanism for formation of cyclic adduct in the proteasome active site.

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Figure 13.12
Figure 13.12

The diarylquinolone bedaquiline inhibits the F subunit of the mycobacterial ATP synthase and deenergizes mycobacterial cells. The adamantyl diamine SQ109 dissipates the electrochemical potential in mycobacterial cells. (Adapted from Li et al. [2014b] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Vignette 13.2
Vignette 13.2

Chambered proteases, including proteasomes and also the ClpP1P2 double ring enzyme forms are potential killing targets in . Isolation of a lasso peptide lassomycin from the previously unculturable sp. nov. validates continued examination of novel culture and antibiotic isolation schemes and that the ClpP chambered proteases are underexplored targets. (Reprinted from Gavrish et al. [2014] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Vignette 13.3
Vignette 13.3

Identification of the mechanism of antibiotic action of nonribosomal peptidolactones of the griselimycin family reveal DNA polymerase, specifically the sliding clamp subunit, is a new target for drug discovery.

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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Image of Figure 13.13
Figure 13.13

-optimized leads for DNA gyrase inhibition. GSK, GlaxoSmithKline; AZ, AstraZeneca.

Citation: Walsh C, Wencewicz T. 2016. Tuberculosis: A Formidable Challenge for Antibiotic Therapy, p 252-271. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch13
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