Binding of ceftaroline to penicillin-binding proteins of Staphylococcus aureus and Streptococcus pneumoniae

Moisan, Hélène; Pruneau, Mireille; Malouin, François

doi:10.1093/jac/dkp503

Cited by 139 publications

(108 citation statements)

References 12 publications

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“…All antibiotics tested had a weak affinity for PBP4 (IC 50 Ͼ 8 g/ml). Moisan et al observed similar weak affinities of ceftaroline and ceftriaxone for PBP4 in strain ATCC 29213 (42). A fluorogram of PBP resolutions in methicillin-susceptible S. aureus ATCC 29213 is presented in Fig.…”

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

confidence: 79%

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

confidence: 79%

“…Previous papers using comparable techniques reported average IC 50 s of 0.16 to 0.9 g/ml for ceftaroline in MRSA strains (27,42,64). Differences between our results and those reported previously (27) may be explained at least partially by differences in strains and culture conditions.…”

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

confidence: 90%

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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“…Van-BDP has been used extensively to detect the location of peptidoglycan synthesis in Gram-positive bacteria (9,14,17,31,39,54). Bocillin FL is a fluorescent penicillin V derivative that binds tightly to penicillin binding proteins (PBPs) (35,59). In control cultures (without daptomycin), Van-BDP intensely stained both complete and incomplete septa and only faintly stained the sidewalls (Fig.…”

Section: Resultsmentioning

confidence: 99%

Daptomycin-Mediated Reorganization of Membrane Architecture Causes Mislocalization of Essential Cell Division Proteins

Pogliano

Silverman

2012

Journal of Bacteriology

292

288

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bDaptomycin is a lipopeptide antibiotic used clinically for the treatment of certain types of Gram-positive infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). Details of the mechanism of action of daptomycin continue to be elucidated, particularly the question of whether daptomycin acts on the cell membrane, the cell wall, or both. Here, we use fluorescence microscopy to directly visualize the interaction of daptomycin with the model Gram-positive bacterium Bacillus subtilis. We show that the first observable cellular effects are the formation of membrane distortions (patches of membrane) that precede cell death by more than 30 min. Membrane patches are able to recruit the essential cell division protein DivIVA. Recruitment of DivIVA correlates with membrane defects and changes in cell morphology, suggesting a localized alteration in the activity of enzymes involved in cell wall synthesis that could account for previously described effects of daptomycin on cell wall morphology and septation. Membrane defects colocalize with fluorescently labeled daptomycin, DivIVA, and fluorescent reporters of peptidoglycan biogenesis (Bocillin FL and BODIPY FL-vancomycin), suggesting that daptomycin plays a direct role in these events. Our results support a mechanism for daptomycin with a primary effect on cell membranes that in turn redirects the localization of proteins involved in cell division and cell wall synthesis, causing dramatic cell wall and membrane defects, which may ultimately lead to a breach in the cell membrane and cell death. These results help resolve the longstanding questions regarding the mechanism of action of this important class of antibiotics.

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“…64 Ceftaroline has antimicrobial activity against MDR Gram-positive bacteria including S. aureus and S. pneumoniae and has up to 256-fold higher affinity for PBP2a than traditional cephalosporins. 65 Interestingly, unhydrolyzed ceftaroline was found to mimic the allosteric activation of PBP2a by PG and promote acylation by a second ceftaroline molecule in the active site [ Fig. 4(B)].…”

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confidence: 99%

One ring to rule them all: Current trends in combating bacterial resistance to the β‐lactams

2016

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From humble beginnings of a contaminated petri dish, b-lactam antibiotics have distinguished themselves among some of the most powerful drugs in human history. The devastating effects of antibiotic resistance have nevertheless led to an "arms race" with disquieting prospects. The emergence of multidrug resistant bacteria threatens an ever-dwindling antibiotic arsenal, calling for new discovery, rediscovery, and innovation in b-lactam research. Here the current state of b-lactam antibiotics from a structural perspective was reviewed.

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Binding of ceftaroline to penicillin-binding proteins of Staphylococcus aureus and Streptococcus pneumoniae

Abstract: The high affinities of ceftaroline for MRSA PBP2a, MSSA PBPs 1-3 and S. pneumoniae PBP2x/2a/2b support the potential efficacy of ceftaroline in the treatment of infections caused by MRSA and S. pneumoniae.

Cited by 139 publications

References 12 publications

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

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

Daptomycin-Mediated Reorganization of Membrane Architecture Causes Mislocalization of Essential Cell Division Proteins

One ring to rule them all: Current trends in combating bacterial resistance to the β‐lactams

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