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Chapter 6 : Other Targets of Antibacterial Drugs

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Abstract:

The sulfa drugs are considered as the longest used class of synthetic chemicals. These drugs were first tested in the 1930s as bacteria-killing molecules. The current generation of sulfa drug is sulfamethoxazole, used in combination with trimethoprim for the treatment of patients with urinary tract infections and also for AIDS patients with infections. This drug pair also validates that combination chemotherapy can be an effective strategy in curing bacterial infections. Each of the drug molecules blocks a step in folic acid metabolism. Thus, the rationale for the combination is synergistic blockade of two different steps in the biochemistry of this essential coenzyme. A set of peptides with antibiotic activity are produced by gram-positive bacteria and are classified as lantibiotics because they all contain the unusual double-headed thioether-containing amino acid lanthionine or its β-methyl lanthionine congener. Rifampin is used clinically only as part of combination regimens for killing the slow-growing pathogen . The drug is an RNA polymerase inhibitor, the only one in clinical use for blocking bacterial transcription. Rifampin binds to the β subunit of the RNA polymerase enzyme at an allosteric site, not at the active site, as defined by resistant mutations in clinical isolates of and . Clinical isolates of rifamycin-resistant have mutations in the β subunit residues that recognize rifamycin, with about three-quarters of the resistance arising from mutations in side chains of residues 406 and 411.

Citation: Walsh C. 2003. Other Targets of Antibacterial Drugs, p 78-88. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch6

Key Concept Ranking

Antibacterial Agents
0.5497424
RNA Polymerase beta Subunit
0.43510035
Antimicrobial Peptides
0.40419284
0.5497424
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Figures

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Untitled

Other validated targets for antibacterial drugs.

Citation: Walsh C. 2003. Other Targets of Antibacterial Drugs, p 78-88. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch6
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Image of Figure 6.1
Figure 6.1

(A) The sulfamethoxazole-trimethoprim combination; (B) the reactions catalyzed by the two target enzymes, dihydropteroate synthase and dihydrofolate reductase.

Citation: Walsh C. 2003. Other Targets of Antibacterial Drugs, p 78-88. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch6
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Image of Figure 6.2
Figure 6.2

The bacterial biosynthetic pathway from GTP to pteroyl-polyglutamate (folate).

Citation: Walsh C. 2003. Other Targets of Antibacterial Drugs, p 78-88. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch6
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Image of Figure 6.3
Figure 6.3

Sulfa drugs as competitive inhibitors and alternate substrates for dihydropteroate synthase.

Citation: Walsh C. 2003. Other Targets of Antibacterial Drugs, p 78-88. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch6
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Figure 6.4

Three-enzyme folate cycle involved in conversion of dUMP to dTMP for DNA biosynthesis.

Citation: Walsh C. 2003. Other Targets of Antibacterial Drugs, p 78-88. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch6
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Image of Figure 6.5
Figure 6.5

(A) Cationic peptide antibiotics that insert into membranes. (B) Schematic for membrane insertion and disruption in gram-negative bacteria (adapted from Hancock and Chapple [1999], with permission). (i) The unfolded cationic peptides associate with the negative charge on the membrane or bind to the cationic binding sites on lipopolysaccharide, to cross the outer membrane. (ii) They then bind to the negative charge on the cytoplasmic membrane surface and the folded, amphipathic peptide inserts into the membrane interface, (iii) aggregating into micelle-like complexes or (iv) flip-flopping across the membrane. Some peptides can then dissociate from the membrane into the cytoplasm.

Citation: Walsh C. 2003. Other Targets of Antibacterial Drugs, p 78-88. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch6
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Image of Figure 6.6
Figure 6.6

Structure of the lipodepsipeptide antibiotic daptomycin.

Citation: Walsh C. 2003. Other Targets of Antibacterial Drugs, p 78-88. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch6
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Image of Figure 6.7
Figure 6.7

(A) Lanthionine and methy lanthionine: key constituents of lantibiotic peptides; (B) five thioether cross-links in the lantibiotic nisin.

Citation: Walsh C. 2003. Other Targets of Antibacterial Drugs, p 78-88. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch6
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Image of Figure 6.8
Figure 6.8

(A) Mersacidin's primary and three-dimensional structure (from Schneider et al. [2000]) and (B) target molecule lipid II.

Citation: Walsh C. 2003. Other Targets of Antibacterial Drugs, p 78-88. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch6
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Image of Figure 6.9
Figure 6.9

Structure of the anti-tuberculosis drug rifampin from the rifamycin family.

Citation: Walsh C. 2003. Other Targets of Antibacterial Drugs, p 78-88. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch6
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Image of Figure 6.10
Figure 6.10

Binding site for rifamycin on its target protein, the subunit of RNA polymerase. (From Campbell et al. [2001].)

Citation: Walsh C. 2003. Other Targets of Antibacterial Drugs, p 78-88. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch6
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