Genetics of resistance to third‐generation cephalosporins in clinical isolates of <i>Streptococcus pneumoniae</i>

Múñoz, Rosario; Dowson, Christopher G.; Daniels, Maggie; Coffey, Tracey J.; Martin, Carine; Hakenbeck, Regine; Spratt, Brian G.

doi:10.1111/j.1365-2958.1992.tb01422.x

Cited by 177 publications

(71 citation statements)

References 20 publications

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“…PBP1a is a major class A bifunctional enzyme and the only pneumococcal class A enzyme implicated in the development of high levels of ␤-lactam resistance (10,39,56). Unlike PBP1a, the absence of the other pneumococcal class A enzymes, PBP2a and PBP1b, did not relieve the requirement for MreC and MreD (Table 4).…”

Section: Discussionmentioning

confidence: 99%

The Requirement for Pneumococcal MreC and MreD Is Relieved by Inactivation of the Gene Encoding PBP1a

2011

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Three basic patterns of peptidoglycan (PG) synthesis have emerged from the study of rod-shaped (bacillus), spherical (coccus), and ellipsoid (ovococcus) bacteria (reviewed in references 12, 71, and 72). In rod-shaped bacteria, like Escherichia coli, Bacillus subtilis, and Caulobacter crescentus, PG synthesis occurs at two locations catalyzed by distinct sets of proteins (12,35,36,71). Lateral PG synthesis elongates the side walls of these bacteria and results in their rod shape (12,35,71). Lateral PG synthesis is mediated by actin-like MreB paralogue proteins, which form filamentous helical structures in spirals over the length of cells (12,35,66). MreB is thought to organize the MreC and MreD proteins, which in turn recruit specific penicillin-binding proteins (PBPs) and other division proteins that catalyze lateral PG formation (26,54,55,70). Septal PG synthesis is organized by FtsZ ring formation, followed by the orderly assembly of the divisome complex, which includes a set of PBPs different from those involved in lateral PG synthesis (16,22,23). The mutational interruption of lateral or septal PG synthesis of rod-shaped bacteria generally results in the formation of spherical or elongated cells, respectively (3, 4, 9, 31). Although useful, this two-state model is obviously an oversimplification (35), and recent results reveal that MreB, MreC, MreD, and specific PBPs also form annular rings adjacent to FtsZ rings at the septa of dividing E. coli cells (67). Moreover, some PBPs and division regulators, such as PBP1 and GpsB of B. subtilis, shuttle between the lateral and septal PG synthesis machineries (9).Much less is known about the mechanisms of PG synthesis in coccus and ovococcus species. In spherical species, such as Staphylococcus aureus, only a septal PG synthesis machinery seems to be present (20,47,72), although S. aureus still encodes homologues of proteins like MreC and MreD that mediate lateral PG synthesis in rod-shaped bacteria (35). In contrast, ovococcus species, such as Streptococcus pneumoniae and Lactococcus lactis, form American football-shaped cells by a combination of peripheral sidewall and septal PG synthesis that occurs in the midcell regions of dividing cells (Fig. 1) (11,42). Ovococcus species lack an MreB homologue, and peripheral and septal PG synthesis are likely coordinated with and organized by FtsZ ring formation (64,65,72). Because two modes of PG biosynthesis are required to form ellipsoidshaped bacteria, models have been proposed for two different PG synthesis machineries (18,21,33,72). Based on the composition of the complexes in rod-shaped cells, it has been hypothesized that specific sets of homologous cell division proteins mediate peripheral (MreC, MreD, RodA, and PBP2b) and septal (FtsZ, EzrA, PBP2x, FtsW, and DivIB/FtsL/DivIC) PG synthesis in ovococcus bacteria (72). A recent study correlating the effects of mutations or antibiotic treatments to changes in cell shapes supports the idea that the PBP2x and PBP2b class B transpeptidases are associated with septal and p...

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Section: Discussionmentioning

confidence: 99%

The Requirement for Pneumococcal MreC and MreD Is Relieved by Inactivation of the Gene Encoding PBP1a

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%

“…Ceftaroline showed a higher affinity for PBP2B than those of ceftriaxone and cefotaxime in the penicillin G-susceptible pneumococcal strain 1076. Low affinities of cefotaxime and ceftriaxone for PBP2B have been described previously (18,24,44).…”

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

162

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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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“…S. pneumoniae R6, whose genome sequence has been determined (Hoskins et al 2001), and one clinical isolate, S. pneumoniae CCRI 1974, were chosen for the laboratory-induced development of resistance to linezolid. Pneumococci were grown in brain heart infusion broth (BHI, Difco) supplemented with 0.5% yeast extract, or in blood agar containing 5% defibrinated sheep's blood as described previously (Munoz et al 1992). Cultures were incubated for 16-24 h in a 5% CO 2 atmosphere at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Genome sequencing of linezolid-resistant Streptococcus pneumoniae mutants reveals novel mechanisms of resistance

Feng¹,

Lupien²,

Gingras³

et al. 2009

Genome Res.

103

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Linezolid is a member of a novel class of antibiotics, with resistance already being reported. We used whole-genome sequencing on three independent Streptococcus pneumoniae strains made resistant to linezolid in vitro in a step-by-step fashion. Analysis of the genome assemblies revealed mutations in the 23S rRNA gene in all mutants including, notably, G2576T, a previously recognized resistance mutation. Mutations in an additional 31 genes were also found in at least one of the three sequenced genomes. We concentrated on three new mutations that were found in at least two independent mutants. All three mutations were experimentally confirmed to be involved in antibiotic resistance. Mutations upstream of the ABC transporter genes spr1021 and spr1887 were correlated with increased expression of these genes and neighboring genes of the same operon. Gene inactivation supported a role for these ABC transporters in resistance to linezolid and other antibiotics. The hypothetical protein spr0333 contains an RNA methyltransferase domain, and mutations within that domain were found in all S. pneumoniae linezolid-resistant strains. Primer extension experiments indicated that spr0333 methylates G2445 of the 23S rRNA and mutations in spr0333 abolished this methylation. Reintroduction of a nonmutated version of spr0333 in resistant bacteria reestablished G2445 methylation and led to cells being more sensitive to linezolid and other antibiotics. Interestingly, the spr0333 ortholog was also mutated in a linezolid-resistant clinical Staphylococcus aureus isolate. Whole-genome sequencing and comparative analyses of S. pneumoniae resistant isolates was useful for discovering novel resistance mutations.

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Genetics of resistance to third‐generation cephalosporins in clinical isolates of Streptococcus pneumoniae

Cited by 177 publications

References 20 publications

The Requirement for Pneumococcal MreC and MreD Is Relieved by Inactivation of the Gene Encoding PBP1a

The Requirement for Pneumococcal MreC and MreD Is Relieved by Inactivation of the Gene Encoding PBP1a

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

Genome sequencing of linezolid-resistant Streptococcus pneumoniae mutants reveals novel mechanisms of resistance

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