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Chapter 7 : Resistance Mediated by Penicillin-Binding Proteins

Author: Malcolm G. P. Page1
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Affiliations: 1: Basilea Pharmaceutica AG, Grenzacherstrasse 487, CH-4005 Basel, Switzerland
Content Type: Monograph
Publication Year: 2007

Category: Bacterial Pathogenesis

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Abstract:

The transpeptidases are members of the family of penicillin-binding proteins (PBPs), which have become known as the targets of β-lactam antibiotics. PBPs perform a variety of critical functions for the bacterial cell. PBPs are found in all pathogenic bacteria except those of the genus , which do not have a cell wall. Reduced expression of PBP2 (type B, assignment not certain) is one of the most frequently observed mechanisms of resistance to carbapenems. PBP2 (type B4) and PBP3 (type B5) have been specifically implicated in resistance towards β-lactams. Increased expression of PBP4 (type C2) has been implicated in resistance to both β-lactams and glycopeptides. Hakenbeck et al. implicated the D,D-carboxypeptidase PBP3 (type C3) in resistance. PCR-based methods for the detection of antibiotic resistance are becoming increasingly important with the expanding use of molecular techniques for bacteriological diagnosis. Antibody-based tests have also been investigated for detection of methicillin resistance in staphylococci. There are several experimental β-lactams now known to be potent inhibitors of the staphylococcal type B1 PBP that is the primary determinant of β-lactam resistance in these organisms, of which ceftobiprole is the most advanced in clinical development. An understanding of the mechanism of methicillin resistance has led to the discovery of accessory factors that influence the level and nature of methicillin resistance.

Citation: Page M. 2007. Resistance Mediated by Penicillin-Binding Proteins, p 81-99. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch7

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Resistance Mediated by Penicillin-Binding Proteins
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Citation: Page M. 2007. Resistance Mediated by Penicillin-Binding Proteins, p 81-99. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch7
/content/10.1128/9781555815615.ch07.ch07fig01
Figure 7.1
Comparison of PBP profiles of selected organisms and pattern alterations commonly encountered in resistant organisms. The PBPs have been labeled by incubation of membranes derived by sonication of cultures of the indicated organisms with radiolabeled benzylpenicillin and then resolution of the proteins by standard sodium dodecyl sulfate-polyacrylamide gel electrophoresis. From left to right:, MRSA, , penicillin susceptible (Pen) and an example of a penicillin-resistant (Pen) isolate where loss of affinity makes some PBPs disappear, and , ampicillin-susceptible (Amp) and an example of an ampicillin-resistant (Amp) isolate where loss of affinity of PBP1 and PBP4 as well as overexpression of PBP5 are evident.
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10.1128/9781555815615/f0082-01.gif
Image of Figure 7.1
Figure 7.1

Comparison of PBP profiles of selected organisms and pattern alterations commonly encountered in resistant organisms. The PBPs have been labeled by incubation of membranes derived by sonication of cultures of the indicated organisms with radiolabeled benzylpenicillin and then resolution of the proteins by standard sodium dodecyl sulfate-polyacrylamide gel electrophoresis. From left to right:, MRSA, , penicillin susceptible (Pen) and an example of a penicillin-resistant (Pen) isolate where loss of affinity makes some PBPs disappear, and , ampicillin-susceptible (Amp) and an example of an ampicillin-resistant (Amp) isolate where loss of affinity of PBP1 and PBP4 as well as overexpression of PBP5 are evident.

Citation: Page M. 2007. Resistance Mediated by Penicillin-Binding Proteins, p 81-99. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch7
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Citation: Page M. 2007. Resistance Mediated by Penicillin-Binding Proteins, p 81-99. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch7
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Figure 7.2
Location of mutations in PBPs conferring resistance to β-lactams. Regions from the sequences of susceptible proteins are shown, with the residues that are mutated in resistant isolates shown in bold and boxed. The highly conserved residues that comprise parts of the active site ( ) are shown in bold. The organisms denoted are (Efc), (Hin), (Hpy), (Nme), (Sau), and (Spn).
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Image of Figure 7.2
Figure 7.2

Location of mutations in PBPs conferring resistance to β-lactams. Regions from the sequences of susceptible proteins are shown, with the residues that are mutated in resistant isolates shown in bold and boxed. The highly conserved residues that comprise parts of the active site ( ) are shown in bold. The organisms denoted are (Efc), (Hin), (Hpy), (Nme), (Sau), and (Spn).

Citation: Page M. 2007. Resistance Mediated by Penicillin-Binding Proteins, p 81-99. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch7
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Tables

Resistance Mediated by Penicillin-Binding Proteins
[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815615.ch07-1,webId=/content/author/10.1128/9781555815615.ch07-1,properties={foaf_givenname=Malcolm G. P., foaf_name=Malcolm G. P. Page, foaf_surname=Page, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815615.ch07-aff1]]}]]
Citation: Page M. 2007. Resistance Mediated by Penicillin-Binding Proteins, p 81-99. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch7
/content/10.1128/9781555815615.ch07.ch07tab01
Table 7.1
Comparison of the PBPs in , and
Generic image for table
Table 7.1

Comparison of the PBPs in , and

Citation: Page M. 2007. Resistance Mediated by Penicillin-Binding Proteins, p 81-99. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch7
/content/10.1128/9781555815615.ch07.ch07tab02
Table 7.2
Comparison of susceptibilities of the PBPs of and to different β-lactam classes
Generic image for table
Table 7.2

Comparison of susceptibilities of the PBPs of and to different β-lactam classes

Citation: Page M. 2007. Resistance Mediated by Penicillin-Binding Proteins, p 81-99. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch7
/content/10.1128/9781555815615.ch07.ch07tab03
Table 7.3
Distribution of PBP types among the bacteria and their contribution to β-lactam resistance
Generic image for table
Table 7.3

Distribution of PBP types among the bacteria and their contribution to β-lactam resistance

Citation: Page M. 2007. Resistance Mediated by Penicillin-Binding Proteins, p 81-99. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch7
/content/10.1128/9781555815615.ch07.ch07tab04
Table 7.4
Kinetic parameters describing the reaction of soluble constructs of PBPs
Generic image for table
Table 7.4

Kinetic parameters describing the reaction of soluble constructs of PBPs

Citation: Page M. 2007. Resistance Mediated by Penicillin-Binding Proteins, p 81-99. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch7
/content/10.1128/9781555815615.ch07.ch07tab05
Table 7.5
Representative anti-MRSA cephalosporins
Generic image for table
Table 7.5

Representative anti-MRSA cephalosporins

Citation: Page M. 2007. Resistance Mediated by Penicillin-Binding Proteins, p 81-99. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch7
/content/10.1128/9781555815615.ch07.ch07tab06
Table 7.6
Anti-MRSA carbapenems
Generic image for table
Table 7.6

Anti-MRSA carbapenems

Citation: Page M. 2007. Resistance Mediated by Penicillin-Binding Proteins, p 81-99. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch7
/content/10.1128/9781555815615.ch07.ch07tab07
Table 7.7
Modulators of PBP2′-mediated resistance in staphylococci
Generic image for table
Table 7.7

Modulators of PBP2′-mediated resistance in staphylococci

Citation: Page M. 2007. Resistance Mediated by Penicillin-Binding Proteins, p 81-99. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch7

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