An Important Site in PBP2x of Penicillin-Resistant Clinical Isolates of
            <i>Streptococcus pneumoniae</i>
            : Mutational Analysis of Thr338

Zerfaß, Ilka; Hakenbeck, Regine; Denapaite, Dalia

doi:10.1128/aac.01107-08

Cited by 31 publications

(40 citation statements)

References 59 publications

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“…Bioinformatic analysis of S. pneumoniae strains whose genomes have been sequenced indicated that the luxS gene is located in a region that contains genes involved in division and cell wall biosynthesis. Specifically, luxS is situated upstream (ϳ6.4 kb) of the gene cps4A (encoding a capsule polysaccharide biosynthesis protein) and ϳ4 kb downstream of the pbp2X gene, whose encoded protein is involved in cell wall biosynthesis and is a target of ␤-lactam antibiotics (30,57), followed by mraY (encoding a phospho-N-acetylmuramoyl-pentapeptide-transferase [ϳ3 kb]) (29) and, ϳ294 bp downstream, the clpL gene, which encodes a putative ATPdependent Clp protease (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

The LuxS-Dependent Quorum-Sensing System Regulates Early Biofilm Formation by Streptococcus pneumoniae Strain D39

et al. 2011

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Streptococcus pneumoniae is the leading cause of death in children worldwide and forms highly organized biofilms in the nasopharynx, lungs, and middle ear mucosa. The luxS-controlled quorum-sensing (QS) system has recently been implicated in virulence and persistence in the nasopharynx, but its role in biofilms has not been studied. Here we show that this QS system plays a major role in the control of S. pneumoniae biofilm formation. Our results demonstrate that the luxS gene is contained by invasive isolates and normal-flora strains in a region that contains genes involved in division and cell wall biosynthesis. The luxS gene was maximally transcribed, as a monocistronic message, in the early mid-log phase of growth, and this coincides with the appearance of early biofilms. Demonstrating the role of the LuxS system in regulating S. pneumoniae biofilms, at 24 h postinoculation, two different D39⌬luxS mutants produced ϳ80% less biofilm biomass than wild-type (WT) strain D39 did. Complementation of these strains with luxS, either in a plasmid or integrated as a single copy in the genome, restored their biofilm level to that of the WT. Moreover, a soluble factor secreted by WT strain D39 or purified AI-2 restored the biofilm phenotype of D39⌬luxS. Our results also demonstrate that during the early mid-log phase of growth, LuxS regulates the transcript levels of lytA, which encodes an autolysin previously implicated in biofilms, and also the transcript levels of ply, which encodes the pneumococcal pneumolysin. In conclusion, the luxS-controlled QS system is a key regulator of early biofilm formation by S. pneumoniae strain D39.

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Section: Resultsmentioning

confidence: 99%

The LuxS-Dependent Quorum-Sensing System Regulates Early Biofilm Formation by Streptococcus pneumoniae Strain D39

et al. 2011

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“…PBP1A and -2X are known to be primary targets for cephalosporins in pneumococci, and all 3 cephalosporins tested showed high affinities for these PBPs, with IC 50 s of Ͻ0.25 g/ml (18,44,63). Ceftaroline showed a higher affinity for PBP2B than those of ceftriaxone and cefotaxime in the penicillin G-susceptible pneumococcal strain 1076.…”

Section: Vol 54 2010 Ceftaroline Affinity For Gram-positive Pbps 1671mentioning

confidence: 99%

Affinity of Ceftaroline and Other β-Lactams for Penicillin-Binding Proteins from Staphylococcus aureus and Streptococcus pneumoniae

Kosowska-Shick

McGhee

Appelbaum

2010

Antimicrob Agents Chemother

163

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We compared the affinities of ceftaroline for all penicillin-binding proteins (PBPs) with those of ceftriaxone and cefotaxime in 6 Staphylococcus aureus and 7 Streptococcus pneumoniae isolates with various resistance phenotypes. Ceftaroline MICs were <1 g/ml against all S. aureus isolates and were <0.25 g/ml for 4 of 7 isolates of S. pneumoniae. Ceftaroline affinities for penicillin-susceptible S. pneumoniae strains were in the order PBP2X and -3 > PBP1A, -1B, and -2A > PBP2B, and ceftaroline had >4-fold higher 50% inhibitory concentrations (IC 50 s) (0.1 to 4 g/ml) for PBP2X, -2A, -2B, and -3 than those for the other cephalosporins tested. Among 3 penicillin-resistant S. pneumoniae strains, ceftaroline had a high affinity for PBP2X (IC 50 , 0.1 to 1 g/ml), a primary target for cephalosporin PBP binding activity, and high affinities for PBP2B (IC 50 , 0.5 to 4 g/ml) and PBP1A (IC 50 , 0.125 to 0.25 g/ml) as well, both of which are also known as major targets for PBP binding activity of cephalosporins. Ceftaroline PBP affinities in methicillin-susceptible S. aureus strains were greater than or equal to those of the 3 other ␤-lactams tested. Ceftaroline bound to PBP2a in methicillinresistant S. aureus (IC 50 , 0.01 to 1 g/ml) with up to 256-fold-higher affinity than those of other agents. Ceftaroline demonstrated very good PBP affinity against all S. aureus and S. pneumoniae strains tested, including resistant isolates.␤-Lactam antibiotics exert their antibacterial effect through covalent interactions with penicillin-binding proteins (PBPs), thus blocking the terminal step in cell wall biosynthesis. ␤-Lactam resistance in Streptococcus pneumoniae is usually caused by amino acid substitutions in the penicillin-binding domains of 1 or more of its 6 PBPs, resulting from point mutations or mosaic genes following recombination (21)(22)(23)35). Altered PBP1A, PBP2X, and PBP2B are the most important PBPs for ␤-lactam resistance among clinical pneumococcal isolates (2,3,31,46,57).In staphylococci, PBPs 1, 2, and 3, which have high affinities for most ␤-lactam antibiotics, are essential for cell growth and survival of methicillin-susceptible strains. Binding of ␤-lactams by these PBPs is lethal (6). Low-molecular-weight PBP4, although it may be important in normal cell wall synthesis and may participate to a limited extent in resistance, is not considered a critical target and may be dispensable (17,41). Methicillin resistance in methicillin-resistant staphylococci (MRSA) is due to expression of a special PBP, PBP2a, which is not present in methicillin-susceptible staphylococci (6,58,59).Ceftaroline fosamil is the developmental intravenous prodrug form of the broad-spectrum cephalosporin ceftaroline (formerly called PPI-0903 M or TAK-91825), which is active against MRSA and has a high affinity for PBP2a (PBP2Ј). It is also active against streptococci, including S. pneumoniae (3,15,16,43,45).In the current study, we determined the affinities of ceftaroline, ceftriaxone, cefotaxime, and penicillin G for PBPs from 6Staphyloco...

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“…However, although knowledge of classical resistance mechanisms is increasing (2,3), understanding of the penicillin heteroresistance phenomenon described in pneumococci remains elusive (4).…”

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confidence: 99%

Heteroresistance to Fosfomycin Is Predominant in Streptococcus pneumoniae and Depends on the murA1 Gene

Engel

Gutiérrez-Fernández

Flückiger

et al. 2013

Antimicrob Agents Chemother

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dFosfomycin targets the first step of peptidoglycan biosynthesis in Streptococcus pneumoniae catalyzed by UDP-N-acetylglucosamine enolpyruvyltransferase (MurA1). We investigated whether heteroresistance to fosfomycin occurs in S. pneumoniae. We found that of 11 strains tested, all but 1 (Hungary 19A ) displayed heteroresistance and that deletion of murA1 abolished heteroresistance. Hungary 19A differs from the other strains by a single amino acid substitution in MurA1 (Ala 364 Thr). To test whether this substitution is responsible for the lack of heteroresistance, it was introduced into strain D39. The heteroresistance phenotype of strain D39 was not changed. Furthermore, no relevant structural differences between the MurA1 crystal structures of heteroresistant strain D39 and nonheteroresistant strain Hungary 19A were found. Our results reveal that heteroresistance to fosfomycin is the predominant phenotype of S. pneumoniae and that MurA1 is required for heteroresistance to fosfomycin but is not the only factor involved. The findings provide a caveat for any future use of fosfomycin in the treatment of pneumococcal infections.

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An Important Site in PBP2x of Penicillin-Resistant Clinical Isolates of Streptococcus pneumoniae : Mutational Analysis of Thr338

Cited by 31 publications

References 59 publications

The LuxS-Dependent Quorum-Sensing System Regulates Early Biofilm Formation by Streptococcus pneumoniae Strain D39

The LuxS-Dependent Quorum-Sensing System Regulates Early Biofilm Formation by Streptococcus pneumoniae Strain D39

Affinity of Ceftaroline and Other β-Lactams for Penicillin-Binding Proteins from Staphylococcus aureus and Streptococcus pneumoniae

Heteroresistance to Fosfomycin Is Predominant in Streptococcus pneumoniae and Depends on the murA1 Gene

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