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Chapter 2 : Major Classes of Antibiotics and Their Modes of Action

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Major Classes of Antibiotics and Their Modes of Action, Page 1 of 2

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Abstract:

Antibiotics are organic molecules usually of low molecular weight (<1,000 daltons) that have antibacterial activity. Depending on the essentiality of the target in bacteria and the mode of action of a given antibiotic, the net effect can lead to killing and is designated . If the molecule inhibits growth and proliferation but does not kill bacteria, it is (Fig. 2.1). For the treatment of clinically significant bacterial infections in humans, bactericidal antibiotics are preferred. However, a bacteriostatic effect may be sufficient for the host immune system to finish the killing process. Agents that eliminate virulence (), which allows pathogens to grow in the host, are effectively bacteriostatic and could allow for the immune system to eradicate the infection.

Citation: Walsh C, Wencewicz T. 2016. Major Classes of Antibiotics and Their Modes of Action, p 16-32. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch2
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Figures

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Figure 2.0

ESKAPE pathogens found in hospitals with multidrug antibiotic resistance (Boucher et al., 2009).

Citation: Walsh C, Wencewicz T. 2016. Major Classes of Antibiotics and Their Modes of Action, p 16-32. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch2
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Figure 2.1

Schematic differentiation of bactericidal, bacteriostatic, and antivirulence antibiotics. The key criterion is whether bacteria are killed or merely stopped from dividing, and the effect depends on the growth conditions. (a) Under test tube conditions in a controlled medium, bacteriostatic agents halt the growth of bacteria while bactericidal agents kill bacteria. Antivirulence antibiotics have no effect on the growth of bacteria in simple nutrient media. (b) When bacterial pathogens are growing within the host, bacteriostatic agents still halt the growth of bacteria and bactericidal agents still kill bacteria. Antivirulence agents behave like bacteriostatic agents within the host and allow the immune system to clear the infection. (Modified from Scholar and Pratt [2000].)

Citation: Walsh C, Wencewicz T. 2016. Major Classes of Antibiotics and Their Modes of Action, p 16-32. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch2
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Image of Figure 2.2
Figure 2.2

Recent antibiotic approvals included nine fluoroquinolones between 2002 and 2014. Structural modifications among the Food and Drug Administration-approved fluoroquinolones are shown in red to highlight the progressive peripheral modification of the fluoroquinolone core scaffold.

Citation: Walsh C, Wencewicz T. 2016. Major Classes of Antibiotics and Their Modes of Action, p 16-32. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch2
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Vignette 2.1

(a) has been found carrying plasmids with up to 45 ARGs! (b) Plasmid pZJ06, isolated from a recent multidrug-resistant (MDR) outbreak strain in China (MDR-ZJ06). This MDR plasmid includes genes for resistance to β-lactams, aminoglycosides, tetracyclines, quinolones, chloramphenicol, and sulfonamides, along with MDR efflux pumps (Zhou et al., 2011).

Citation: Walsh C, Wencewicz T. 2016. Major Classes of Antibiotics and Their Modes of Action, p 16-32. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch2
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Figure 2.3

Antibiotic discovery: two ways to measure MIC values. (a) Plate assay with potential growth inhibitor(s) (antibiotic) placed on a disc in a lawn of bacteria ( in this plate). Increasing concentrations of antibiotic give larger zones of inhibition, affected by time and diffusion constants. (b) MIC determination in liquid cultures using 96-well plate format.

Citation: Walsh C, Wencewicz T. 2016. Major Classes of Antibiotics and Their Modes of Action, p 16-32. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch2
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Figure 2.4

Three classes of synthetic antibiotics in human clinical use: sulfonamides, introduced in the 1930s; fluoroquinolones, introduced in 1960; and oxazolidinones, introduced in the 1990s.

Citation: Walsh C, Wencewicz T. 2016. Major Classes of Antibiotics and Their Modes of Action, p 16-32. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch2
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Figure 2.5

The golden age of antibiotic discovery encompassed 1940 to 1960, when most of the classes still in use today were introduced. The golden age of medicinal chemistry has ensued over the subsequent 50 years, involving tailoring of the periphery of each major antibiotic class while leaving the core scaffold intact and functional.

Citation: Walsh C, Wencewicz T. 2016. Major Classes of Antibiotics and Their Modes of Action, p 16-32. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch2
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Image of Figure 2.6
Figure 2.6

The β-lactam antibiotics all have the thermodynamically activated four-membered lactam as the chemical warhead. Penicillins have the lactam fused to a five-membered thiane ring (4,5-fused bicycle); cephalosporins have an expanded 4,6-fused bicyclic scaffold. Carbapenems have the sulfur atom replaced by carbon. The conversion of naturally occurring penicillin N and cephalosporin C to semisynthetic antibiotics is facilitated by enzymatic deacylation of the aminoadipoyl group to yield 6-APA and 7-ACA, respectively, reacylatable with synthetic side chains as exemplified by amoxicillin and cephalothin.

Citation: Walsh C, Wencewicz T. 2016. Major Classes of Antibiotics and Their Modes of Action, p 16-32. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch2
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Image of Figure 2.7
Figure 2.7

Multiple generations of four antibiotic classes: cephalosporins, quinolones, macrolides, and tetracyclines. Boxed columns show generations of semisynthetic (fully synthetic in the case of quinolones) variants introduced to combat waves of resistant bacterial pathogens, up to contemporary fourth- and fifth-generation molecules. The chart is a testimony to the skill of medicinal chemists over the past 50 years to keep ahead of life-threatening drug-resistant bacteria. The pentacyclines have not yet progressed through clinical trials (Wright et al., 2014).

Citation: Walsh C, Wencewicz T. 2016. Major Classes of Antibiotics and Their Modes of Action, p 16-32. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch2
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Image of Figure 2.8
Figure 2.8

Five classes of bacterial machinery comprise the targets of the major classes of antibiotics: (a) cell wall biosynthesis, (b) protein biosynthesis, (c) macromolecular synthesis (DNA and RNA) and metabolism, (d) the folate biosynthetic pathway (interdicting the supply of deoxythymidylate for DNA synthesis), and (e) membrane function. DHP, dihydropteroate; DHF, dihydrofolate; THF, tetrahydrofolate. (Reprinted from Walsh and Wencewicz [2014] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Major Classes of Antibiotics and Their Modes of Action, p 16-32. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch2
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Image of Figure 2.9
Figure 2.9

Antibiotics of different classes with distinct targets are proposed to alter balance in bacterial metabolism, respiration, and iron homeostasis that can set off increased flux of oxidants and radicals that synergize to contribute to bacterial cell death. (Adapted from Dwyer et al. [2014].)

Citation: Walsh C, Wencewicz T. 2016. Major Classes of Antibiotics and Their Modes of Action, p 16-32. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch2
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References

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Tables

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Table 2.1

Bacterial pathogens cause a variety of infectious diseases

Citation: Walsh C, Wencewicz T. 2016. Major Classes of Antibiotics and Their Modes of Action, p 16-32. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch2
Generic image for table
Table 2.2

Natural antibiotic classes in human clinical use

Citation: Walsh C, Wencewicz T. 2016. Major Classes of Antibiotics and Their Modes of Action, p 16-32. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch2

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