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Genetics and molecular biology of beta-lactam-resistant pneumococci
T J Coffey1, C G Dowson, M Daniels
1Microbial Genetics Group, School of Biological Sciences, University of Sussex, Brighton, UK.
Abstract:
Penicillin-resistant pneumococci have been reported with increasing frequency in recent years. Isolates with high-level resistance are now found in many countries, and in some countries they constitute a substantial proportion of all isolates. A worrying development is the recent emergence of pneumococci with high-level resistance to third-generation cephalosporins. Resistance to beta-lactam antibiotics in pneumococci is due entirely to the development of altered forms of the high-molecular-weight penicillin-binding proteins (PBPs) that have decreased affinity for the antibiotics. High-level resistance to third-generation cephalosporins has occurred by the development of altered forms of PBP1a and 2x, whereas high-level penicillin resistance additionally requires alterations of PBP2b. Altered PBPs are encoded by mosaic genes that have emerged by recombinational events between the pbp genes of pneumococci and their homologs in closely related streptococcal species. Horizontal gene transfer, presumably mediated by genetic transformation, has also resulted in the dissemination of altered pbp genes, and possibly capsular biosynthetic genes, between different pneumococcal lineages to produce new resistant clones.
Insights
Penicillin-resistant Streptococcus pneumoniae strains are increasing globally. Altered penicillin-binding proteins (PBPs) drive resistance to beta-lactam antibiotics, including third-generation cephalosporins, through gene modification and horizontal gene transfer.
Area of Science:
- Microbiology
- Molecular Biology
- Genetics
Background:
- Increasing prevalence of penicillin-resistant Streptococcus pneumoniae globally.
- Emergence of high-level resistance to third-generation cephalosporins in pneumococci.
- Resistance mechanisms in pneumococci are linked to alterations in penicillin-binding proteins (PBPs).
Purpose of the Study:
- To investigate the genetic basis of emerging antibiotic resistance in Streptococcus pneumoniae.
- To understand the molecular mechanisms underlying resistance to beta-lactam antibiotics, including cephalosporins.
- To explore the role of altered PBPs and gene transfer in the dissemination of resistant pneumococcal strains.
Main Methods:
- Analysis of altered penicillin-binding protein (PBP) genes in resistant pneumococcal isolates.
- Investigation of mosaic gene formation through recombinational events with related streptococcal species.
- Assessment of horizontal gene transfer, likely via genetic transformation, in the spread of resistance genes.
Main Results:
- High-level penicillin resistance involves alterations in PBP2b, PBP1a, and PBP2x.
- High-level resistance to third-generation cephalosporins is associated with altered PBP1a and PBP2x.
- Mosaic PBP genes arise from recombination between pneumococcal and homologous streptococcal genes.
- Horizontal gene transfer facilitates the spread of altered PBP genes and potentially capsular genes, creating new resistant clones.
Conclusions:
- Altered penicillin-binding proteins (PBPs) are the primary cause of beta-lactam antibiotic resistance in Streptococcus pneumoniae.
- The emergence of resistance to third-generation cephalosporins is a significant concern, driven by specific PBP alterations.
- Recombination and horizontal gene transfer are key mechanisms for the evolution and dissemination of antibiotic-resistant pneumococcal strains.