compensatory evolution of pbp mutations restores the fitness cost imposed by β-lactam resistance in streptococcus pneumoniae补偿pbp突变的进化恢复健身成本由β-lactam耐药性肺炎链球菌.pdf

Compensatory Evolution of pbp Mutations Restores the Fitness Cost Imposed by b-Lactam Resistance in Streptococcus pneumoniae ´ ´ ˜ ´ Andrea G. Albarracın Orio, German E. Pinas, Paulo R. Cortes, Melina B. Cian, Jose Echenique* ´ ´ ´ ´ ´ Departamento de Bioquımica Clınica - CIBICI (CONICET), Facultad de Ciencias Quımicas, Universidad Nacional de Cordoba, Cordoba, 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, b-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 b-lactam resistance. This report describes a direct correlation between antibiotic resistance increase and fitness cost compensation, both caused by the same gene mutations