Interaction of Ceftobiprole with the Low-Affinity PBP 5 of
            <i>Enterococcus faecium</i>

Henry, Xavier; Amoroso, Ana Maria; Coyette, Jacques; Joris, Bernard

doi:10.1128/aac.00983-09

Cited by 21 publications

(16 citation statements)

References 18 publications

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“…2) and that the low-molecular-mass PBP6, a D, D-carboxypeptidase (16), was not affected. This inhibition pattern is completely different from that obtained with benzylpenicillin, for which PBP5 is the most resistant PBP (17). The IC 50 s for ceftaroline on PBP5 were 1.40 Ϯ 0.09 mg/liter and 0.7 mg/liter when determined with membrane preparations and the purified sPBP5, respectively.…”

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confidence: 77%

“…The kinetic parameters governing the acylation of PBP5 by ceftaroline were determined by using the sPBP5 (a soluble PBP5 from which the N-terminal membrane anchoring peptide was removed), which was overproduced and purified as previously described, except that the molecular sieve step was eliminated (18). The kinetics model used has been described previously (17). On the basis of the data shown in Fig.…”

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confidence: 99%

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Activity of Ceftaroline against Enterococcus faecium PBP5

Henry

Verlaine

Amoroso

et al. 2013

Antimicrob Agents Chemother

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The opportunistic human pathogen Enterococcus faecium overproduces the low-affinity PBP5. In clinical strains, mutations in PBP5 further reduce its acylation rate by ␤-lactams. Previous studies have reported that ceftaroline had poor inhibitory activity against ␤-lactam-resistant E. faecium strains. In this study, we show that ceftaroline exhibits killing activity against our laboratory-derived ampicillin-resistant E. faecium mutant that overproduces a wild-type PBP5 and that ceftaroline inactivates PBP5 much faster than benzylpenicillin and faster than ceftobiprole. ␤ -Lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams) represent the most important group of drugs prescribed to treat bacterial infections. They form stable acyl-enzymes with their targets, the membrane-bound D, D-transpeptidases, which are essential enzymes in peptidoglycan biosynthesis. These proteins are usually referred to as penicillin-binding proteins (PBPs) (1-3). The presence or overproduction of loweraffinity PBPs is responsible for the resistance of Gram-positive cocci against ␤-lactam antibiotics. It is known that the opportunistic human pathogen Enterococcus faecium overproduces the low-affinity PBP5 and that mutations further reduce the acylation rate of PBP5 by altering its amino acid sequence (4, 5). Ceftaroline is a cephalosporin with broad-spectrum activity against Grampositive organisms, including methicillin-resistant Staphylococcus aureus (MRSA), and many common Gram-negative bacteria except those producing extended-spectrum ␤-lactamase (ESBL) or AmpC ␤-lactamase (6-8). The Staphylococcus aureus low-affinity PBP2a is closely related to PBP5 (9). It is inhibited by ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, which was recently approved by the U.S. Food and Drug Administration (FDA) for use in adult patients with acute bacterial skin and skinstructure infections and community-acquired bacterial pneumonia and more recently approved by the European Medicines Agency (EMA) for similar indications (10, 11). Previous studies have reported that ceftaroline had poor inhibitory activity against ␤-lactam-resistant E. faecium strains, all of which were expected to possess a PBP5 protein (6,12). To better understand these differences, we have characterized the interaction between a wild-type form of PBP5 and ceftaroline.Ceftaroline MIC values determined by the microdilution method (13) for E. faecium D63r and D63 strains (5) were 2 and 0.25 mg · liter Ϫ1 , respectively. These values contrasted with those reported by others (10-12), who have found that most ampicillinresistant E. faecium clinical isolates were resistant to ceftaroline and concluded that ceftaroline had little activity against most isolates of E. faecium. The killing effects (14) of ceftaroline on E. faecium D63 and D63r strains were studied by exposing exponentially growing cultures of both strains to increasing concentrations of antibiotics corresponding to 1 and 4 times their respective MICs (Fig. 1). Ceftaroline showed k...

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confidence: 77%

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confidence: 99%

Activity of Ceftaroline against Enterococcus faecium PBP5

Henry

Verlaine

Amoroso

et al. 2013

Antimicrob Agents Chemother

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“…Ceftobiprole shows great potential for the treatment of E. faecium infections and was found to efficiently acylate resistant PBP5. 74 Of the six PBPs from Streptococcus pneumoniae PBP1a, PBP2b, PBP2x, and sometimes PBP2a were found to contain resistance mutations in clinical isolates. PBP1a, PBP2b, and PBP2x were found to be mosaic genes in the majority of resistant isolates.…”

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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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“…Their activities are beyond all other cephalosporins and appear to be less susceptible to develop resistance. Ceftobiprole exhibits a high level of affinity for PBPs of MRSA [12].…”

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Computational Calculations of Molecular Properties and Molecular Docking of New and Reference Cephalosporins on Penicillin Binding Proteins and Various β-Lactamases

Alwan¹

2016

JPP

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An approach of using molinspiration calculations and molecular docking on PBPs (penicillin-binding proteins) and certain β-lactamases is employed to predict the molecular properties, bioactivity and resistance of newer and reference cephalosporins. The previously synthesized cephalosporins 1-8 and reference cephalosporins were subjected to extensive evaluations by calculating the molecular properties, drug-likeness scores on the bases of Lipinski's rule and bioactivity prediction using the method of molinspiration web-based software. The TPSA (topological polar surface area), OH-NH interactions, n-violation and the molinspiration Log partition coefficient (miLogP) values were also calculated. The investigated cephalosporins were subjected to molecular docking study on PBPs (1pyy) and on β-lactamases produced by S. aureus, K. pneumonia, E. coli and P. auroginosa using 1-click-docking website. Molecular properties of 1-8 recorded higher TPSA than cephalexin and were lower than the reference cephalosporins and do not fulfill the requirements for Lipinski's rule. Bioactivities of 1-8 were predicted to be less and their docking scores on PBPs were comparable to those of the reference cephalosporins, particularly ceftobiprole. The references recorded various docking scores on the above β-lactamases and as expected, ceftobiprole recorded the lowest scores on all β-lactamases. Cephalosporins 1-8 recorded various docking scores on β-lactamases. Molecular docking studies on PBPs and β-lactamases are considered as very useful, reliable and practical approach for predicting the bioactivity scores and to afford some information about the stability and selectivity of the newly proposed cephalosporins against β-lactamases of certain pathogenic microbes, such as P. auroginosa and MRSA, by recording the relative docking scores in comparison with those of reference cephalosporins.

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Interaction of Ceftobiprole with the Low-Affinity PBP 5 of Enterococcus faecium

Cited by 21 publications

References 18 publications

Activity of Ceftaroline against Enterococcus faecium PBP5

Activity of Ceftaroline against Enterococcus faecium PBP5

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

Computational Calculations of Molecular Properties and Molecular Docking of New and Reference Cephalosporins on Penicillin Binding Proteins and Various β-Lactamases

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