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Chapter 21 : Mechanisms for Penicillin Resistance in : Penicillin-Binding Proteins, Gene Transfer, and Cell Wall Metabolism

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Abstract:

Penicillin resistance in has been studied in the laboratory since the early 1940s, long before it became an actual problem in clinical isolates in the late 1970s. Intraspecies gene transfer of penicillin-binding proteins (PBPs) variants between commensal streptococci and the pathogen appears to be responsible for the emergence of clinical isolates and guarantees efficient spread between clones of the pathogen. Methicillin-resistant organisms become completely susceptible to beta-lactams upon disruption of the genes (for factor essential for methicillin resistance). In view of the fact that PBP2b is encoded by an essential chromosomal gene, it may prove difficult to dilute it out of the bacterial population even without the selective pressure of beta-lactam therapy. Mosaic genes are the result of gene transfer events followed by recombination into the chromosome. In order to find genes that are potential ancestors of the mosaic blocks, pbp2x genes in closely related commensal streptococci were investigated. Examination of laboratory mutants demonstrated the complexity of resistance development with respect to PBP mutations. Two different beta-lactam antibiotics were used to select for spontaneous, independent mutant families that consisted of members with increasing resistance levels: piperacillin, a highly lytic penicillin that interacts with all PBPs at low concentrations, and cefotaxime, which does not interact with PBP2b. A non-PBP-mediated mechanism has been suggested for a high-level resistant Hungarian clone, but its molecular nature remains to be identified.

Citation: Bergmann C, Chi F, Rachid S, Hakenbeck R. 2004. Mechanisms for Penicillin Resistance in : Penicillin-Binding Proteins, Gene Transfer, and Cell Wall Metabolism, p 339-349. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch21

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Teichoic Acid Biosynthesis
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Cell Wall Biosynthesis
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Figures

Image of FIGURE 1
FIGURE 1

PBPs in beta-lactam-resistant . (A) Cell lysates were incubated with [H]propionylampicillin, proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and PBP–beta-lactam complexes were visualized after fluorography. The six PBPs present in the sensitive parental strain R6 (lanes 2, 7, and 9) are marked on the right. The arrowheads indicate low-affinity PBP variants. Strains were laboratory mutants selected with piperacillin (lane 1) and cefotaxime (lanes 3 and 4) and beta-lactam-resistant transformants of the R6 strain, obtained with chromosomal DNA of a high-level beta-lactam-resistant strain and selection with piperacillin (lane 5), cefotaxime (lane 6), and four rounds of transformation and selection with cefotaxime and benzylpenicillin (lane 8). (B) MICs and altered PBPs of the strains shown in panel A. No mutation in PBP1a occurs in the mutant shown in lane 1, although the apparent amount of PBP1a is reduced (white arrowhead).

Citation: Bergmann C, Chi F, Rachid S, Hakenbeck R. 2004. Mechanisms for Penicillin Resistance in : Penicillin-Binding Proteins, Gene Transfer, and Cell Wall Metabolism, p 339-349. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch21
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Image of FIGURE 2
FIGURE 2

Mosaic structure of genes in clones. The genetic relatedness of clones was calculated on the basis of their multilocus sequence type data using the split-tree program. The patterns in the genes indicate the relationship of altered sequence blocks; the blocks themselves are not shown. Genes marked in black contain one highly related mosaic block that covers the penicillin-binding domain and various portions of the gene encoding the N- and C-terminal parts of the protein; it is identical in size and sequence in the two clones marked by the arrows. The genes with the checkered pattern are all identical in sequence. The gene of the one penicillin-sensitive clone has no mosaic structure and is shown in white.

Citation: Bergmann C, Chi F, Rachid S, Hakenbeck R. 2004. Mechanisms for Penicillin Resistance in : Penicillin-Binding Proteins, Gene Transfer, and Cell Wall Metabolism, p 339-349. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch21
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Image of FIGURE 3
FIGURE 3

Mosaic block structure of genes and mutations associated with resistance. White indicates sequences of sensitive strains. Divergent sequences representing mosaic blocks are shown in black independent of their relatedness. The positions of the active-site motifs are shown at the top. The arrows above the conserved motifs indicate amino acid substitutions that have been shown to be associated with resistance phenotype (T338, M339, H394, T550, Q552). Altered positions in the mosaic genes are marked by white bars across the gene. The positions of mutations identified in cefotaxime-resistant laboratory mutants are indicated at the bottom. The region covering the central penicillin-binding domain is marked by grey shading.

Citation: Bergmann C, Chi F, Rachid S, Hakenbeck R. 2004. Mechanisms for Penicillin Resistance in : Penicillin-Binding Proteins, Gene Transfer, and Cell Wall Metabolism, p 339-349. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch21
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