Penicillin-binding components of penicillin-susceptible and -resistant strains of Streptococcus pneumoniae

Percheson, P. B.; Bryan, L. E.

doi:10.1128/aac.18.3.390

Cited by 44 publications

(20 citation statements)

References 22 publications

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“…␤-Lactam resistance in pneumococcal disease isolates is due to combinations of altered PBPs that have decreased affinities for these antibiotics (94,95). These strains invariably reveal profound changes in corresponding key PBP genes, and a very wide range of "resistant" PBP gene alleles have been documented (96)(97)(98)(99).…”

Section: Peptidoglycan Synthesis and Penicillin-binding Proteinsmentioning

confidence: 99%

Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: a United States Perspective

et al. 2016

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SUMMARYStreptococcus pneumoniaeinflicts a huge disease burden as the leading cause of community-acquired pneumonia and meningitis. Soon after mainstream antibiotic usage, multiresistant pneumococcal clones emerged and disseminated worldwide. Resistant clones are generated through adaptation to antibiotic pressures imposed while naturally residing within the human upper respiratory tract. Here, a huge array of related commensal streptococcal strains transfers core genomic and accessory resistance determinants to the highly transformable pneumococcus. β-Lactam resistance is the hallmark of pneumococcal adaptability, requiring multiple independent recombination events that are traceable to nonpneumococcal origins and stably perpetuated in multiresistant clonal complexes. Pneumococcal strains with elevated MICs of β-lactams are most often resistant to additional antibiotics. Basic underlying mechanisms of most pneumococcal resistances have been identified, although new insights that increase our understanding are continually provided. Although all pneumococcal infections can be successfully treated with antibiotics, the available choices are limited for some strains. Invasive pneumococcal disease data compiled during 1998 to 2013 through the population-based Active Bacterial Core surveillance program (U.S. population base of 30,600,000) demonstrate that targeting prevalent capsular serotypes with conjugate vaccines (7-valent and 13-valent vaccines implemented in 2000 and 2010, respectively) is extremely effective in reducing resistant infections. Nonetheless, resistant non-vaccine-serotype clones continue to emerge and expand.

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Section: Peptidoglycan Synthesis and Penicillin-binding Proteinsmentioning

confidence: 99%

Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: a United States Perspective

et al. 2016

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“…In clinical isolates of S. pneumoniae, penicillin resistance is due to the development of high-molecular-weight penicillin-binding proteins (PBPs) that have a greatly reduced affinity for the antibiotic (8,21). Highly penicillin-resistant isolates (MIC, >1 ,g of benzylpenicillin per ml) may have alterations to at least four of the five high-molecular-weight PBPs.…”

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Genetics of oxacillin resistance in clinical isolates of Streptococcus pneumoniae that are oxacillin resistant and penicillin susceptible

Dowson

Johnson

Cercenado

et al. 1994

Antimicrob Agents Chemother

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It has recently been reported that penicillin-sensitive pneumococci may exhibit reduced susceptibility to oxacillin, resulting in their misclassification as being penicillin resistant by oxacillin disk testing. Intermediate oxacillin resistance (MIC, 1.0 microgram/ml) in three of these apparently unrelated penicillin-susceptible clinical isolates of Streptococcus pneumoniae isolated in the United Kingdom and in four Spanish isolates was shown to be solely due to the acquisition of a gene encoding an altered penicillin-binding protein (PBP), PBP2X. PBP2X genes cloned from typical penicillin-resistant isolates of S. pneumoniae that possessed high-level oxacillin resistance were shown to be able to transform susceptible isolates of S. pneumoniae to intermediate oxacillin resistance. In all instances, the intermediately oxacillin-resistant PBP2X transformants retained susceptibility to penicillin (MIC, 0.06 microgram/ml). Under appropriate selective pressure, the acquisition of a low-affinity PBP2X by penicillin-susceptible pneumococci could result in an increasing number of false positives for penicillin resistance among isolates of S. pneumoniae screened with oxacillin. Additionally, these intermediately oxacillin-resistant isolates showed reduced susceptibility to cefotaxime, an agent likely to be prescribed in place of penicillin for the treatment of serious infections due to these apparently penicillin-resistant organisms.

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Five independent combinations of mutations can result in low-affinity penicillin-binding protein 2x of Streptococcus pneumoniae

Laible

Hakenbeck

1991

J Bacteriol

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Penicillin-binding protein 2x (PBP 2x) Intrinsic penicillin resistance in pneumococci and various other pathogenic bacteria is mediated by the production of low-penicillin-affinity variants of essential high-molecularweight penicillin-binding proteins (PBPs), the target proteins of ,-lactam antibiotics (11,25,30,34). These PBPs are believed to be essential enzymes functioning during late stages of murein biosynthesis. They interact with ,-lactams by enzymatically forming a covalent penicilloyl (cephalosporoyl) complex which is enzymatically inactive. ,3-Lactams are recognized by PBPs because of their structural similarity to substrate molecules (i.e., muropeptides), and inhibitors as well as substrates interact with the same active-site serine (for a review, see reference 8). Therefore, mutations responsible for low affinity must be carefully positioned within the protein in order to still allow for its actual in vivo function.We have recently isolated a series of spontaneous, independent mutants with stepwise increasing resistance to cefotaxime (17). All higher-level-resistance mutants contained low-affinity variants of PBP 2x and, in some cases, of PBP 2a as well. Reduction in the penicillin binding of PBP 2x at ddiferent selection steps was detected when mutants from different mutant families were compared, indicating that the development of resistance does not follow a strictly predetermined pathway.The gene coding for the 750-amino-acid PBP 2x (pbpX) has been sequenced, and the mutations in one of the mutants (C506) have been mapped (18). We have now determined the sequence of mutations that occurred with increasing cefotaxime resistance in one mutant family and analyzed their contribution to resistance development. Furthermore, mutations in the pbpX genes of another four independent mutants, obtained after five or six selection steps, were characterized.* Corresponding author. MATERIALS AND METHODSBacterial strains, phages, and plasmids. The penicillinsusceptible laboratory strain Streptococcus pneumoniae R6 is an unencapsulated derivative of the Rockefeller University strain R36A (1). The cefotaxime-resistant mutants, all derived from the R6 strain, are independent, spontaneous mutants, as described previously (17). The mutant family C006 is composed of six mutants with increasing levels of resistance, from C106 (first-step isolate) to C606 (sixth-step isolate). Mutants C501, C503, C604, and C505 were obtained after five or six selection steps (indicated by the first digit) in mutant families 1, 3, 4, and 5, respectively (indicated by the last digit).The phages Phagescript SK (Stratagene, San Diego, Calif.) and M13mp8/9 (22) were propagated in Escherichia coli JM103 (21), and derivatives of the plasmids pJDC9 (4) and pR28 (20) were propagated in E. coli DH5. Transformation of S. pneumoniae (32) and of E. coli (3) followed published procedures.Isolation of DNA. Details of the isolation of chromosomal DNA and the preparation of phage and plasmid DNA have been described recently (2, 18).Isolation and sequ...

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Penicillin-binding components of penicillin-susceptible and -resistant strains of Streptococcus pneumoniae

Cited by 44 publications

References 22 publications

Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: a United States Perspective

Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: a United States Perspective

Genetics of oxacillin resistance in clinical isolates of Streptococcus pneumoniae that are oxacillin resistant and penicillin susceptible

Five independent combinations of mutations can result in low-affinity penicillin-binding protein 2x of Streptococcus pneumoniae

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