Deletion analysis of the essentiality of penicillin-binding proteins 1A, 2B and 2X of<i>Streptococcus pneumoniae</i>

Kell, Christopher M.; Sharma, Uday; Dowson, Christopher G.; Town, C.; Balganesh, Tanjore S.; Spratt, Brian G.

doi:10.1111/j.1574-6968.1993.tb05954.x

Cited by 67 publications

(7 citation statements)

References 19 publications

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“…Since the pbp2a mutant did not phenocopy gpsB depletion, and given the complex network of GpsB interactions in B. subtilis and L. monocytogenes , we also sought to extend the pneumococcal GpsB interactome starting from those proteins that were reported to form a complex with Sp GpsB by co-immunoprecipitation (co-IP) 24 . Besides the Sp GpsB interactions detected with Sp PBP2a and Sp MreC by BACTH, we also detected an interaction between Sp GpsB and the essential class B Sp PBP2x 44 (Supplementary Figure 6A). Sp PBP2x, which contains a cytoplasmic domain abundant with arginines, also interacted with Sp GpsB in FP experiments (Supplementary Figure 6B).…”

Section: Resultsmentioning

confidence: 71%

The cell cycle regulator GpsB functions as cytosolic adaptor for multiple cell wall enzymes

et al. 2019

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Bacterial growth and cell division requires precise spatiotemporal regulation of the synthesis and remodelling of the peptidoglycan layer that surrounds the cytoplasmic membrane. GpsB is a cytosolic protein that affects cell wall synthesis by binding cytoplasmic mini-domains of peptidoglycan synthases to ensure their correct subcellular localisation. Here, we describe critical structural features for the interaction of GpsB with peptidoglycan synthases from three bacterial species (Bacillus subtilis, Listeria monocytogenes and Streptococcus pneumoniae) and suggest their importance for cell wall growth and viability in L. monocytogenes and S. pneumoniae. We use these structural motifs to identify novel partners of GpsB in B. subtilis and extend the members of the GpsB interactome in all three bacterial species. Our results support that GpsB functions as an adaptor protein that mediates the interaction between membrane proteins, scaffolding proteins, signalling proteins and enzymes to generate larger protein complexes at specific sites in a bacterial cell cycle-dependent manner.

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Section: Resultsmentioning

confidence: 71%

The cell cycle regulator GpsB functions as cytosolic adaptor for multiple cell wall enzymes

et al. 2019

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“…The involvement of these three PBPs in peptidoglycan expansion/cell shaping and cell division dictates that two (PBP2b and PBP2x) are also essential for cell viability (104), making it difficult to dissect specific steps in the acquisition of resistance. Although pbp1a can be inactivated under laboratory conditions, resulting in profound phenotypic defects (104), it undoubtedly serves irreplaceable roles in nature.…”

Section: Peptidoglycan Synthesis and Penicillin-binding Proteinsmentioning

confidence: 99%

“…Although pbp1a can be inactivated under laboratory conditions, resulting in profound phenotypic defects (104), it undoubtedly serves irreplaceable roles in nature. The requirement of these PBPs for viability dictates that there are fitness costs associated with the development of pneumococcal ␤-lactam resistance.…”

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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“…In resistant clinical strains of S. pneumoniae, up to five PBPs are phenotypically altered in ␤-lactam low-affinity variants: PBPs 1a, 1b, 2a, 2x, and 2b (4, 10 -12). PBP2x and PBP2b are essential for cellular growth (13) and are primary targets for ␤-lactams (14). Therefore, a detailed understanding of the structural modifications conferring the ␤-lactam resistance properties of these two PBPs is a crucial step in designing new ␤-lactam antibiotics.…”

mentioning

confidence: 99%

Mutations in the Active Site of Penicillin-binding Protein PBP2x from Streptococcus pneumoniae

Mouz

Guilmi

Gordón

et al. 1999

Journal of Biological Chemistry

102

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Penicillin-binding protein 2x (PBP2x) isolated from clinical beta-lactam-resistant strains of Streptococcus pneumoniae (R-PBP2x) have a reduced affinity for beta-lactam antibiotics. Their transpeptidase domain carries numerous substitutions compared with homologous sequences from beta-lactam-sensitive streptococci (S-PBP2x). Comparison of R-PBP2x sequences suggested that the mutation Gln552 --> Glu is important for resistance development. Mutants selected in the laboratory with cephalosporins frequently contain a mutation Thr550 --> Ala. The high resolution structure of a complex between S-PBP2x* and cefuroxime revealed that Gln552 and Thr550, which belong to strand beta3, are in direct contact with the cephalosporin. We have studied the effect of alterations at positions 552 and 550 in soluble S-PBP2x (S-PBP2x*) expressed in Escherichia coli. Mutation Q552E lowered the acylation efficiency for both penicillin G and cefotaxime when compared with S-PBP2x*. We propose that the introduction of a negative charge in strand beta3 conflicts with the negative charge of the beta-lactam. Mutation T550A lowered the acylation efficiency of the protein for cefotaxime but not for penicillin G. The in vitro data presented here are in agreement with the distinct resistance profiles mediated by these mutations in vivo and underline their role as powerful resistance determinants.

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Deletion analysis of the essentiality of penicillin-binding proteins 1A, 2B and 2X ofStreptococcus pneumoniae

Cited by 67 publications

References 19 publications

The cell cycle regulator GpsB functions as cytosolic adaptor for multiple cell wall enzymes

The cell cycle regulator GpsB functions as cytosolic adaptor for multiple cell wall enzymes

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

Mutations in the Active Site of Penicillin-binding Protein PBP2x from Streptococcus pneumoniae

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