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Chapter 8 : Mechanisms of Drug Resistance in Mycobacterium tuberculosis

Authors: Ying Zhang1, William R. Jacobs, Jr., Catherine Vilchèze
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Affiliations: 1: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205
Content Type: Monograph
Publication Year: 2005

Category: Bacterial Pathogenesis; Clinical Microbiology

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Abstract:

Drug resistance in tuberculosis (TB) is a particular problem because the lengthy therapy of at least 6 months makes patient compliance very difficult, which frequently creates drug-resistant strains of . This chapter provides an update on genes associated with drug resistance and the current understanding of mechanisms of drug resistance and drug action in . The emergence of drug resistance in bacteria is one of the easiest demonstrations of the "survival of the fittest" concept of Darwin's theory of evolution. Resistance is thus due to a change in the genotype resulting in a drug-resistant phenotype of a bacterium, which can be passed on to subsequent generations. This is in contrast to tolerance, or phenotypic resistance, another phenomenon that is common to and other bacterial species, in which changes in the metabolic or physiological status of the cell induce temporary drug resistance as seen in stationary-phase, starved, or dormant bacteria. Knowledge about the mutations conferring drug resistance not only leads to understanding of the mechanisms of drug resistance and drug action but also facilitates rapid detection of drug resistance by molecular means. Phenotypic resistance is a major problem for antibiotic therapy, especially for TB. Nongrowing bacteria can be divided roughly into two different types depending on whether they grow immediately on subculture into a defined fresh medium.

Citation: Zhang Y, Jacobs, Jr. W, Vilchèze C. 2005. Mechanisms of Drug Resistance in Mycobacterium tuberculosis, p 115-140. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch8
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Mechanisms of Drug Resistance in Mycobacterium tuberculosis
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Citation: Zhang Y, Jacobs, Jr. W, Vilchèze C. 2005. Mechanisms of Drug Resistance in Mycobacterium tuberculosis, p 115-140. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch8
/content/10.1128/9781555817657.chap8.fig8-1
Figure 1

Structures of first-line and some second-line TB drugs.

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10.1128/9781555817657/fig8-1.gif
Image of Figure 1
Figure 1

Structures of first-line and some second-line TB drugs.

Citation: Zhang Y, Jacobs, Jr. W, Vilchèze C. 2005. Mechanisms of Drug Resistance in Mycobacterium tuberculosis, p 115-140. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch8
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Figure 2

Mode of action of INH. INH enters tubercle bacilli by passive diffusion and is activated by KatG to a range of reactive species. These reactive species or radicals, which include both reactive oxygen species (hydrogen peroxide, superoxide, peroxynitrite, and hydroxyl radical) and organic radicals attack multiple targets, e.g., mycolic acid synthesis, DNA damage, and NAD metabolism in the cell. The isonicotinoyl acyl radical reacts with NAD_ to form an INH-NAD adduct, which inhibits the enoyl-ACP reductase InhA of the FASII system. Inhibition of InhA results in mycolic acid biosynthesis inhibition and ultimately in cell lysis. Deficient efflux and insufficient antagonism of INH-derived radicals, such as a defective anti-oxidative defense, may underlie the unique susceptibility of to INH.

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10.1128/9781555817657/fig8-2.gif
Image of Figure 2
Figure 2

Mode of action of INH. INH enters tubercle bacilli by passive diffusion and is activated by KatG to a range of reactive species. These reactive species or radicals, which include both reactive oxygen species (hydrogen peroxide, superoxide, peroxynitrite, and hydroxyl radical) and organic radicals attack multiple targets, e.g., mycolic acid synthesis, DNA damage, and NAD metabolism in the cell. The isonicotinoyl acyl radical reacts with NAD_ to form an INH-NAD adduct, which inhibits the enoyl-ACP reductase InhA of the FASII system. Inhibition of InhA results in mycolic acid biosynthesis inhibition and ultimately in cell lysis. Deficient efflux and insufficient antagonism of INH-derived radicals, such as a defective anti-oxidative defense, may underlie the unique susceptibility of to INH.

Citation: Zhang Y, Jacobs, Jr. W, Vilchèze C. 2005. Mechanisms of Drug Resistance in Mycobacterium tuberculosis, p 115-140. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch8
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Figure 3

Mode of action of PZA.

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10.1128/9781555817657/fig8-3.gif
Image of Figure 3
Figure 3

Mode of action of PZA.

Citation: Zhang Y, Jacobs, Jr. W, Vilchèze C. 2005. Mechanisms of Drug Resistance in Mycobacterium tuberculosis, p 115-140. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch8
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Tables

Mechanisms of Drug Resistance in Mycobacterium tuberculosis
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Citation: Zhang Y, Jacobs, Jr. W, Vilchèze C. 2005. Mechanisms of Drug Resistance in Mycobacterium tuberculosis, p 115-140. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch8
/content/10.1128/9781555817657.chap8.tab8-1
Table 1

Mechanisms of drug action and resistance in mycobacteria

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10.1128/9781555817657/tab8-1.gif
Generic image for table
Table 1

Mechanisms of drug action and resistance in mycobacteria

Citation: Zhang Y, Jacobs, Jr. W, Vilchèze C. 2005. Mechanisms of Drug Resistance in Mycobacterium tuberculosis, p 115-140. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch8