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Compensatory evolution of pbp mutations restores the fitness cost imposed by β-lactam resistance in Streptococcus pneumoniae.

Albarracín Orio AG, Piñas GE, Cortes PR, Cian MB, Echenique J - PLoS Pathog. (2011)

Bottom Line: Thus, these compensatory combinations of pbp mutant alleles resulted in an increase in the level and spectrum of β-lactam resistance.The clinical origin of the pbp mutations suggests that this intergenic compensatory process is involved in the persistence of β-lactam resistance among circulating strains.We propose that this compensatory mechanism is relevant for β-lactam resistance evolution in Streptococcus pneumoniae.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Bioquímica Clínica - CIBICI (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.

ABSTRACT
The prevalence of antibiotic resistance genes in pathogenic bacteria is a major challenge to treating many infectious diseases. The spread of these genes is driven by the strong selection imposed by the use of antibacterial drugs. However, in the absence of drug selection, antibiotic resistance genes impose a fitness cost, which can be ameliorated by compensatory mutations. In Streptococcus pneumoniae, β-lactam resistance is caused by mutations in three penicillin-binding proteins, PBP1a, PBP2x, and PBP2b, all of which are implicated in cell wall synthesis and the cell division cycle. We found that the fitness cost and cell division defects conferred by pbp2b mutations (as determined by fitness competitive assays in vitro and in vivo and fluorescence microscopy) were fully compensated by the acquisition of pbp2x and pbp1a mutations, apparently by means of an increased stability and a consequent mislocalization of these protein mutants. Thus, these compensatory combinations of pbp mutant alleles resulted in an increase in the level and spectrum of β-lactam resistance. This report describes a direct correlation between antibiotic resistance increase and fitness cost compensation, both caused by the same gene mutations acquired by horizontal transfer. The clinical origin of the pbp mutations suggests that this intergenic compensatory process is involved in the persistence of β-lactam resistance among circulating strains. We propose that this compensatory mechanism is relevant for β-lactam resistance evolution in Streptococcus pneumoniae.

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Correlation plot between the fitness value of pbp mutants, obtained by using pbp genes from Cba-19 and Cba-28 clinical strains, and the penicillin MIC increase found (µg/ml).A) Correlation for Cp1015 pbp19 mutants, Cp1015 pbp2b19 (diamonds), Cp1015 pbp2b19 pbp2x19 (triangles), and Cp1015 pbp2b19 pbp1a19 pbp2x19 (circles). B) Correlation for Cp1015 pbp28 mutants, Cp1015 pbp2b28 (diamonds), Cp1015 pbp2b28pbp2x28 (triangles), and Cp1015 pbp2b28 pbp2x28 pbp1a28 (circles).
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ppat-1002000-g001: Correlation plot between the fitness value of pbp mutants, obtained by using pbp genes from Cba-19 and Cba-28 clinical strains, and the penicillin MIC increase found (µg/ml).A) Correlation for Cp1015 pbp19 mutants, Cp1015 pbp2b19 (diamonds), Cp1015 pbp2b19 pbp2x19 (triangles), and Cp1015 pbp2b19 pbp1a19 pbp2x19 (circles). B) Correlation for Cp1015 pbp28 mutants, Cp1015 pbp2b28 (diamonds), Cp1015 pbp2b28pbp2x28 (triangles), and Cp1015 pbp2b28 pbp2x28 pbp1a28 (circles).

Mentions: All findings about compensation of growth alterations were similar to the results obtained by competitive fitness assays in vitro, when comparing the βL-susceptible Cp1015 strain with isogenic pbp mutants. The compensatory effect among pbp mutations was evident not only in triple, but also in pbp2b19 pbp1a19, pbp2b19 pbp2x19, pbp2b28 pbp1a28, and pbp2b9V3 pbp2x9V3 double mutants, recovering their values of relative fitness of 0.95–1.10 in the case of the triple pbp mutants (Table 1). We also observed that single pbp1a mutations obtained from Cba-19 and Cba-28 increased fitness in the wild-type strains (Table 1), and therefore should be considered as increasing-fitness mutations. Interestingly, we found a direct correlation between fitness compensation and an increase in the spectrum and level of βL resistance (Fig. 1; Table 1).


Compensatory evolution of pbp mutations restores the fitness cost imposed by β-lactam resistance in Streptococcus pneumoniae.

Albarracín Orio AG, Piñas GE, Cortes PR, Cian MB, Echenique J - PLoS Pathog. (2011)

Correlation plot between the fitness value of pbp mutants, obtained by using pbp genes from Cba-19 and Cba-28 clinical strains, and the penicillin MIC increase found (µg/ml).A) Correlation for Cp1015 pbp19 mutants, Cp1015 pbp2b19 (diamonds), Cp1015 pbp2b19 pbp2x19 (triangles), and Cp1015 pbp2b19 pbp1a19 pbp2x19 (circles). B) Correlation for Cp1015 pbp28 mutants, Cp1015 pbp2b28 (diamonds), Cp1015 pbp2b28pbp2x28 (triangles), and Cp1015 pbp2b28 pbp2x28 pbp1a28 (circles).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040684&req=5

ppat-1002000-g001: Correlation plot between the fitness value of pbp mutants, obtained by using pbp genes from Cba-19 and Cba-28 clinical strains, and the penicillin MIC increase found (µg/ml).A) Correlation for Cp1015 pbp19 mutants, Cp1015 pbp2b19 (diamonds), Cp1015 pbp2b19 pbp2x19 (triangles), and Cp1015 pbp2b19 pbp1a19 pbp2x19 (circles). B) Correlation for Cp1015 pbp28 mutants, Cp1015 pbp2b28 (diamonds), Cp1015 pbp2b28pbp2x28 (triangles), and Cp1015 pbp2b28 pbp2x28 pbp1a28 (circles).
Mentions: All findings about compensation of growth alterations were similar to the results obtained by competitive fitness assays in vitro, when comparing the βL-susceptible Cp1015 strain with isogenic pbp mutants. The compensatory effect among pbp mutations was evident not only in triple, but also in pbp2b19 pbp1a19, pbp2b19 pbp2x19, pbp2b28 pbp1a28, and pbp2b9V3 pbp2x9V3 double mutants, recovering their values of relative fitness of 0.95–1.10 in the case of the triple pbp mutants (Table 1). We also observed that single pbp1a mutations obtained from Cba-19 and Cba-28 increased fitness in the wild-type strains (Table 1), and therefore should be considered as increasing-fitness mutations. Interestingly, we found a direct correlation between fitness compensation and an increase in the spectrum and level of βL resistance (Fig. 1; Table 1).

Bottom Line: Thus, these compensatory combinations of pbp mutant alleles resulted in an increase in the level and spectrum of β-lactam resistance.The clinical origin of the pbp mutations suggests that this intergenic compensatory process is involved in the persistence of β-lactam resistance among circulating strains.We propose that this compensatory mechanism is relevant for β-lactam resistance evolution in Streptococcus pneumoniae.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Bioquímica Clínica - CIBICI (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.

ABSTRACT
The prevalence of antibiotic resistance genes in pathogenic bacteria is a major challenge to treating many infectious diseases. The spread of these genes is driven by the strong selection imposed by the use of antibacterial drugs. However, in the absence of drug selection, antibiotic resistance genes impose a fitness cost, which can be ameliorated by compensatory mutations. In Streptococcus pneumoniae, β-lactam resistance is caused by mutations in three penicillin-binding proteins, PBP1a, PBP2x, and PBP2b, all of which are implicated in cell wall synthesis and the cell division cycle. We found that the fitness cost and cell division defects conferred by pbp2b mutations (as determined by fitness competitive assays in vitro and in vivo and fluorescence microscopy) were fully compensated by the acquisition of pbp2x and pbp1a mutations, apparently by means of an increased stability and a consequent mislocalization of these protein mutants. Thus, these compensatory combinations of pbp mutant alleles resulted in an increase in the level and spectrum of β-lactam resistance. This report describes a direct correlation between antibiotic resistance increase and fitness cost compensation, both caused by the same gene mutations acquired by horizontal transfer. The clinical origin of the pbp mutations suggests that this intergenic compensatory process is involved in the persistence of β-lactam resistance among circulating strains. We propose that this compensatory mechanism is relevant for β-lactam resistance evolution in Streptococcus pneumoniae.

Show MeSH
Related in: MedlinePlus