1887

Chapter 8 : Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria

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

Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817886/9781555818937_Chap08-1.gif /docserver/preview/fulltext/10.1128/9781555817886/9781555818937_Chap08-2.gif

Abstract:

Enzymatic inactivation of antibiotics occurs with several of the natural product antibiotic classes but has not yet been observed as a major route of resistance development for the classes of synthetic antibacterials: the sulfamethoxazole-trimethoprim combination, the fluoroquinolones, or the oxazolidinones. The most widespread mode of clinical resistance development to β-lactam antibiotics is the expression of β-lactamases that hydrolyze the antibiotic. Two approaches have been taken in the decades since lactam-resistant clinical isolates began to diminish the efficacy of penicillins and cephalosporins as antibiotics. The first has been to develop semisynthetic β-lactams which were slower substrates for attack by the hydrolytic lactamases. The second approach has been to screen for inhibitors and inactivators of lactamase activity and then combine these molecules with a β-lactam. β-Lactamase genes can be embedded in bacterial chromosomes, such as the gene in enteric bacteria or the gene in , or they can be carried on multiple-copy plasmids or transposons, as is the case for the TEM-1 bla gene in a variety of high-level penicillin-resistant gram-negative bacteria found in clinical isolates. In the ampG, ampD, and ampR genes control expression of the ampC-encoding β-lactamase. In external penicillin leads to an increase in autolytic peptidoglycan hydrolase activity and subsequent vulnerability to osmotic lysis and death. Three kinds of enzymatic modifications of OH and NH groups on aminoglycosides are common determinants of resistance and represent variants of normal electrophilic group transfer enzymes that participate in primary metabolism.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8

Key Concept Ranking

beta-Lactam Antibiotics
0.59230095
Klebsiella pneumoniae
0.49339956
0.59230095
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria
Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
/content/10.1128/9781555817886.chap8.fig8-pg106
Untitled

Modification of antibiotics by resistant bacteria

10.1128/9781555817886/fig-pg106_thmb.gif
10.1128/9781555817886/fig-pg106.gif
Image of Untitled
Untitled

Modification of antibiotics by resistant bacteria

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-1
Figure 8.1

Hydrolytic ring opening and deactivation of (A) penicillins, (B) cephalosporins, and (C) carbapenems by -lactamases.

10.1128/9781555817886/fig8-1_thmb.gif
10.1128/9781555817886/fig8-1.gif
Image of Figure 8.1
Figure 8.1

Hydrolytic ring opening and deactivation of (A) penicillins, (B) cephalosporins, and (C) carbapenems by -lactamases.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-2
Figure 8.2

Structures of class A, C, and D -lactamases and homology to the fold of a D,Dpeptidase (PBP). (Figure provided courtesy of J. Knox.)

10.1128/9781555817886/fig8-2_thmb.gif
10.1128/9781555817886/fig8-2.gif
Image of Figure 8.2
Figure 8.2

Structures of class A, C, and D -lactamases and homology to the fold of a D,Dpeptidase (PBP). (Figure provided courtesy of J. Knox.)

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-3
Figure 8.3

Hydrolysis of the -lactam ring of penicillins by class A, C, and D lactamases involves covalent penicilloyl enzyme intermediates, while the class B zinc-dependent lactamases carry out direct attack by water.

10.1128/9781555817886/fig8-3_thmb.gif
10.1128/9781555817886/fig8-3.gif
Image of Figure 8.3
Figure 8.3

Hydrolysis of the -lactam ring of penicillins by class A, C, and D lactamases involves covalent penicilloyl enzyme intermediates, while the class B zinc-dependent lactamases carry out direct attack by water.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-4
Figure 8.4

Different half-lives for the acyl--Ser enzyme intermediates control the outcomes with penicilloyl-PBPs versus penicilloyl--lactamases.

10.1128/9781555817886/fig8-4_thmb.gif
10.1128/9781555817886/fig8-4.gif
Image of Figure 8.4
Figure 8.4

Different half-lives for the acyl--Ser enzyme intermediates control the outcomes with penicilloyl-PBPs versus penicilloyl--lactamases.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-5
Figure 8.5

-Lactamases in bacterial periplasms hydrolyze penicillins and cephalosporins before they reach their target PBPs at the outer face of the cytoplasmic membrane. TPase/TGase, bifunctional transpeptidase/transglycosylase.

10.1128/9781555817886/fig8-5_thmb.gif
10.1128/9781555817886/fig8-5.gif
Image of Figure 8.5
Figure 8.5

-Lactamases in bacterial periplasms hydrolyze penicillins and cephalosporins before they reach their target PBPs at the outer face of the cytoplasmic membrane. TPase/TGase, bifunctional transpeptidase/transglycosylase.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-6
Figure 8.6

Structural modifications in the acyl side chains of -lactam antibiotics to build in slow processing by -lactamases. X-ray analysis of extended-spectrum -lactam antibiotics with -lactamase cocrystals shows that the bulky side chain provides a severe steric block to proper positioning of water in the deacylation step and accounts for the very low s for enzymatic hydrolysis.

10.1128/9781555817886/fig8-6_thmb.gif
10.1128/9781555817886/fig8-6.gif
Image of Figure 8.6
Figure 8.6

Structural modifications in the acyl side chains of -lactam antibiotics to build in slow processing by -lactamases. X-ray analysis of extended-spectrum -lactam antibiotics with -lactamase cocrystals shows that the bulky side chain provides a severe steric block to proper positioning of water in the deacylation step and accounts for the very low s for enzymatic hydrolysis.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-7
Figure 8.7

Isomerization in the ring-opened acyl enzyme form of the carbapenem thienamycin during destruction by -lactamase slows net hydrolysis.

10.1128/9781555817886/fig8-7_thmb.gif
10.1128/9781555817886/fig8-7.gif
Image of Figure 8.7
Figure 8.7

Isomerization in the ring-opened acyl enzyme form of the carbapenem thienamycin during destruction by -lactamase slows net hydrolysis.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-8
Figure 8.8

Clavulanate, sulbactam, and tazobactam: mechanism-based inactivators of -lactamases.

10.1128/9781555817886/fig8-8_thmb.gif
10.1128/9781555817886/fig8-8.gif
Image of Figure 8.8
Figure 8.8

Clavulanate, sulbactam, and tazobactam: mechanism-based inactivators of -lactamases.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-9
Figure 8.9

Rerouting of the acyl enzyme intermediate by clavulanate and penicillin sulfone to inactivate -lactamases.

10.1128/9781555817886/fig8-9_thmb.gif
10.1128/9781555817886/fig8-9.gif
Image of Figure 8.9
Figure 8.9

Rerouting of the acyl enzyme intermediate by clavulanate and penicillin sulfone to inactivate -lactamases.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-10
Figure 8.10

The anhydromuramyl tripeptide signaling pathway for induction of expression in ; transport into the cytoplasm by AmpG and ligation to AmpR to relieve transcriptional repression of ; and secretion of AmpC into the periplasm.

10.1128/9781555817886/fig8-10_thmb.gif
10.1128/9781555817886/fig8-10.gif
Image of Figure 8.10
Figure 8.10

The anhydromuramyl tripeptide signaling pathway for induction of expression in ; transport into the cytoplasm by AmpG and ligation to AmpR to relieve transcriptional repression of ; and secretion of AmpC into the periplasm.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-11
Figure 8.11

The operon of and the signal transduction pathway for expression of the BlaZ lactamase in : tandem proteolysis of BlaR1 and BlaI for gene activation.

10.1128/9781555817886/fig8-11_thmb.gif
10.1128/9781555817886/fig8-11.gif
Image of Figure 8.11
Figure 8.11

The operon of and the signal transduction pathway for expression of the BlaZ lactamase in : tandem proteolysis of BlaR1 and BlaI for gene activation.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-12
Figure 8.12

Signal transduction logic for regulated expression of the MecA PBP2A to confer methicillin resistance in MRSA.

10.1128/9781555817886/fig8-12_thmb.gif
10.1128/9781555817886/fig8-12.gif
Image of Figure 8.12
Figure 8.12

Signal transduction logic for regulated expression of the MecA PBP2A to confer methicillin resistance in MRSA.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-13
Figure 8.13

Three enzymatic routes to aminoglycoside deactivation: acetylation by acetyl- CoA, phosphorylation by ATP, and adenylation by ATP.

10.1128/9781555817886/fig8-13_thmb.gif
10.1128/9781555817886/fig8-13.gif
Image of Figure 8.13
Figure 8.13

Three enzymatic routes to aminoglycoside deactivation: acetylation by acetyl- CoA, phosphorylation by ATP, and adenylation by ATP.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-14
Figure 8.14

Patterns of regioselective enzymatic modification and deactivation of aminoglycoside antibiotics. NT, nucleotidyl transfer; PO, phosphoryl transfer; Ac, acetyl transfer.

10.1128/9781555817886/fig8-14_thmb.gif
10.1128/9781555817886/fig8-14.gif
Image of Figure 8.14
Figure 8.14

Patterns of regioselective enzymatic modification and deactivation of aminoglycoside antibiotics. NT, nucleotidyl transfer; PO, phosphoryl transfer; Ac, acetyl transfer.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555817886.chap8.fig8-15
Figure 8.15

Enzymatic deactivation of fosfomycin by epoxide ring opening with glutathione.

10.1128/9781555817886/fig8-15_thmb.gif
10.1128/9781555817886/fig8-15.gif
Image of Figure 8.15
Figure 8.15

Enzymatic deactivation of fosfomycin by epoxide ring opening with glutathione.

Citation: Walsh C. 2003. Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, p 106-123. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555817886.chap8

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