1887

Chapter 10 : Antibiotic Resistance by Replacement or Modification of the Antibiotic Target

Author: Christopher Walsh
Content Type: Monograph
Publication Year: 2003

Category: Bacterial Pathogenesis

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Preview Magnify
Zoom in
Zoomout

Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817886/9781555818937_Chap10-1.gif /docserver/preview/fulltext/10.1128/9781555817886/9781555818937_Chap10-2.gif

Abstract:

One of the routes to clinically important resistance in pathogenic bacteria is the ability of drug-resistant pathogens to modify the drug target to insensitivity while still retaining its essential cellular function. This chapter exemplifies the principles of antibiotic resistance arising from replacement or modification of the target. This can be achieved by mutation at one or more sites in the target gene or by importation of a gene that specifies a new replacement enzyme that has markedly decreased sensitivity to the drug. β-lactam resistance in the grampositive and strains represent these two variations on a theme. Unlike the strains and many other pathogens, does not use β-lactamases as the major route to penicillin resistance. Analysis of transpeptidases/transglycosylases in reveal five high-molecular-weight PBPs which contribute to killing by β-lactams. One of the goals of medicinal chemistry in developing broad-spectrum erythromycin family of macrolides is to overcome the Erm phenotypes by creating semisynthetic or altered versions of the macrolides that can still bind to methylated A versions of the 23S rRNA. Telithromycin has recently been approved for human use and ABT-773 is in advanced clinical evaluation. species account for about 90 to 95% of vancomycin-resistant clinical isolates and another 5%, with minor species accounting for the rest. There had been few therapeutic choices for vancomycin-resistant enterococci (VRE) treatment, but the recent approvals of both the Synercid combination and the oxazolidinone linezolid indicate efficacy against VRE.

Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Antibiotic Resistance by Replacement or Modification of the Antibiotic Target
Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
/content/10.1128/9781555817886.chap10.fig10-pg142
Untitled

Antibiotic resistance by modification of the target.

10.1128/9781555817886/fig-pg142_thmb.gif
10.1128/9781555817886/fig-pg142.gif
Image of Untitled
Untitled

Antibiotic resistance by modification of the target.

Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap10.fig10-1
Figure 10.1

Gram-positive pathogens that become drug resistant by target alterations: (A) in a blood culture; (B) encapsulated , including (a) gram-positive diplococci surrounded by a capsule and (b) a polymorphonuclear leukocyte with multilobed nucleus; (C) Gram stain of sputum of patient with pneumonia; (D) “golden” colonies on blood agar plates. (From Elliot et al. [1997], with permission.)

10.1128/9781555817886/fig10-1_thmb.gif
10.1128/9781555817886/fig10-1.gif
Image of Figure 10.1
Figure 10.1

Gram-positive pathogens that become drug resistant by target alterations: (A) in a blood culture; (B) encapsulated , including (a) gram-positive diplococci surrounded by a capsule and (b) a polymorphonuclear leukocyte with multilobed nucleus; (C) Gram stain of sputum of patient with pneumonia; (D) “golden” colonies on blood agar plates. (From Elliot et al. [1997], with permission.)

Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap10.fig10-2
Figure 10.2

Structure of methicillin.

10.1128/9781555817886/fig10-2_thmb.gif
10.1128/9781555817886/fig10-2.gif
Image of Figure 10.2
Figure 10.2

Structure of methicillin.

Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap10.fig10-3
Figure 10.3

Carbapenems with activity against MRSA: (A) molecules with aryl side chain substituents; (B) release of the immunogenic side chain of carbapenem L-786,392 on attack of the -lactam by the active-site serine of PBP2A.

10.1128/9781555817886/fig10-3_thmb.gif
10.1128/9781555817886/fig10-3.gif
Image of Figure 10.3
Figure 10.3

Carbapenems with activity against MRSA: (A) molecules with aryl side chain substituents; (B) release of the immunogenic side chain of carbapenem L-786,392 on attack of the -lactam by the active-site serine of PBP2A.

Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap10.fig10-4
Figure 10.4

Structure of 3-ketolides telithromycin and ABT-773, broad-spectrum erythromycin derivatives.

10.1128/9781555817886/fig10-4_thmb.gif
10.1128/9781555817886/fig10-4.gif
Image of Figure 10.4
Figure 10.4

Structure of 3-ketolides telithromycin and ABT-773, broad-spectrum erythromycin derivatives.

Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap10.fig10-5
Figure 10.5

Incidence of VRE in intensive care units (shaded bars) and nonintensive care units (unshaded bars) in the early 1990s. From (Hughes and Tenover [1997], with permission.)

10.1128/9781555817886/fig10-5_thmb.gif
10.1128/9781555817886/fig10-5.gif
Image of Figure 10.5
Figure 10.5

Incidence of VRE in intensive care units (shaded bars) and nonintensive care units (unshaded bars) in the early 1990s. From (Hughes and Tenover [1997], with permission.)

Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap10.fig10-6
Figure 10.6

A five-gene cluster is necessary and sufficient to confer the VanA and VanB phenotypes of VRE.

10.1128/9781555817886/fig10-6_thmb.gif
10.1128/9781555817886/fig10-6.gif
Image of Figure 10.6
Figure 10.6

A five-gene cluster is necessary and sufficient to confer the VanA and VanB phenotypes of VRE.

Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap10.fig10-7
Figure 10.7

Reprogramming of the PG termini from -Ala--Ala to -Ala--lactate by the three-enzyme cassette VanH-VanA-VanX; role of VanX and MurF in partitioning of -Ala--Ala versus -Ala--Lac for destruction or elongation.

10.1128/9781555817886/fig10-7_thmb.gif
10.1128/9781555817886/fig10-7.gif
Image of Figure 10.7
Figure 10.7

Reprogramming of the PG termini from -Ala--Ala to -Ala--lactate by the three-enzyme cassette VanH-VanA-VanX; role of VanX and MurF in partitioning of -Ala--Ala versus -Ala--Lac for destruction or elongation.

Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap10.fig10-8
Figure 10.8

Loss of one hydrogen bond between vancomycin and -Ala--lactate provides a 1,000-fold drop in binding affinity.

10.1128/9781555817886/fig10-8_thmb.gif
10.1128/9781555817886/fig10-8.gif
Image of Figure 10.8
Figure 10.8

Loss of one hydrogen bond between vancomycin and -Ala--lactate provides a 1,000-fold drop in binding affinity.

Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap10.fig10-9
Figure 10.9

PG--Ala--Lac termini are substrates for transpeptidase-mediated cross-linking.

10.1128/9781555817886/fig10-9_thmb.gif
10.1128/9781555817886/fig10-9.gif
Image of Figure 10.9
Figure 10.9

PG--Ala--Lac termini are substrates for transpeptidase-mediated cross-linking.

Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap10.fig10-10
Figure 10.10

(A) X-ray structures of the -Ala--Ala ligase from , the -Ala--Lac ligase from , and the VanA -Ala--Lac ligase from . (B) The phosphorylation of the dialkylphosphinate analog in the active site of the ligase produces a transition-state analog that behaves like a slow, tight-binding inhibitor. (C) Active-site architecture of DdlB with ADP and phosphophosphinate bound. (From Shi and Walsh [1995], with permission.)

10.1128/9781555817886/fig10-10_thmb.gif
10.1128/9781555817886/fig10-10.gif
Image of Figure 10.10
Figure 10.10

(A) X-ray structures of the -Ala--Ala ligase from , the -Ala--Lac ligase from , and the VanA -Ala--Lac ligase from . (B) The phosphorylation of the dialkylphosphinate analog in the active site of the ligase produces a transition-state analog that behaves like a slow, tight-binding inhibitor. (C) Active-site architecture of DdlB with ADP and phosphophosphinate bound. (From Shi and Walsh [1995], with permission.)

Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap10.fig10-11
Figure 10.11

Proposal for the VanS-VanR sensor kinase / response regulator to turn on the , , and genes to reprogram peptidoglycan biosynthesis.

10.1128/9781555817886/fig10-11_thmb.gif
10.1128/9781555817886/fig10-11.gif
Image of Figure 10.11
Figure 10.11

Proposal for the VanS-VanR sensor kinase / response regulator to turn on the , , and genes to reprogram peptidoglycan biosynthesis.

Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555817886.chap10

Tables

Antibiotic Resistance by Replacement or Modification of the Antibiotic Target
Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10
/content/10.1128/9781555817886.chap10.tab10-1
Table 10.1

Phenotypes of glycopeptide-resistant enterococci

Generic image for table
Table 10.1

Phenotypes of glycopeptide-resistant enterococci

Citation: Walsh C. 2003. Antibiotic Resistance by Replacement or Modification of the Antibiotic Target, p 142-156. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch10

Back to top
This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error