Binding of Ceftobiprole and Comparators to the Penicillin-Binding Proteins of
 Escherichia coli
 ,
 Pseudomonas aeruginosa
 ,
 Staphylococcus aureus
 , and
 Streptococcus pneumoniae

Davies, Todd A.; Page, Malcolm G. P.; Shang, Wenchi; Andrew, Ted; Kania, Malgosia; Bush, Karen

doi:10.1128/aac.00029-07

Cited by 150 publications

(139 citation statements)

References 28 publications

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“…Our data show that acidic pH causes a significant change in conformational behavior of PBP 2a, rendering it more susceptible to ␤-lactams. In terms of mechanistic consequence, we assert that these observations are quite similar to those recently reported for new cephalosporins that are capable of inhibiting PBP 2a effectively, arguing for an underlying principal that governs both cases (22)(23)(24).…”

Section: Methicillin-resistant Staphylococcus Aureus (Mrsa)supporting

confidence: 68%

Restoration of Susceptibility of Methicillin-resistant Staphylococcus aureus to β-Lactam Antibiotics by Acidic pH

Lemaire

Fuda

Bambeke

et al. 2008

Journal of Biological Chemistry

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Methicillin-resistant Staphylococcus aureus (MRSA) is a global scourge, and treatment options are becoming limited. The MRSA phenotype reverts to that of ␤-lactam-sensitive S. aureus when bacteria are grown at pH 5.0 in broth and, more importantly from a medical perspective (protracted, relapsing infections), after phagocytosis by macrophages, where the bacteria thrive in the acidic environment of phagolysosomes. The central factor for the MRSA phenotype is the function of the penicillin-binding protein (PBP) 2a, which maintains transpeptidase activity while being poorly inhibited by ␤-lactams because of a closed conformation of its active site. We document herein by binding, acylation/deacylation kinetics, and circular dichroism spectroscopy with purified PBP 2a that at acidic pH (i) ␤-lactams interact with PBP 2a more avidly; (ii) the non-covalent pre-acylation complex exhibits a lower dissociation constant and an increased rate of acyl-enzyme formation (first-order rate constant) without change in hydrolytic deacylation rate; and (iii) PBP 2a undergoes a conformational change in the presence of the antibiotic consistent with the opening of the active site from the closed conformation. These observations argue that PBP 2a most likely evolved for its physiological function at pH 7 or higher by adopting a closed conformation, which is not maintained at acidic pH. Although at the organism level the effect of acidic pH on other biological processes in MRSA could not be discounted, our report should provide the impetus for closer examination of the properties of PBP 2a at low pH and thereby identifying novel points of intervention in combating this problematic organism.

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Section: Methicillin-resistant Staphylococcus Aureus (Mrsa)supporting

confidence: 68%

Restoration of Susceptibility of Methicillin-resistant Staphylococcus aureus to β-Lactam Antibiotics by Acidic pH

Lemaire

Fuda

Bambeke

et al. 2008

Journal of Biological Chemistry

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“…All ceftobiprole MIC values were 2 µg/mL for 146 isolates of S. aureus including MSSA (MIC 90 , 1 µg/mL) and MRSA (MIC 90 , 2 µg/mL). Denis et al 6 reported ceftobiprole MIC 50 and MIC 90 values of 0.5 and 2 µg/mL, respectively against MRSA. Of a total of 1201 S. aureus (66% MRSA) and 460 CNS single-patient isolates, ceftobiprole MICs ranged from 0.12 to 1 µg/mL for MSSA and 0.25 to 4 µg/mL for MRSA.…”

Section: Staphylococcus Speciesmentioning

confidence: 99%

“…Ceftobiprole exhibits a binding profile similar to those of cefepime and ceftazidime in Pseudomonas aeruginosa but with an enhanced binding to PBP2. 6 This profile contributes to the broad-spectrum antibacterial activity against gram-negative and grampositive bacteria of this cephalosporin. No breakpoints have been established for ceftobiprole, but based on minimum inhibitory concentration (MIC) distribution and pharmacokinetic/pharmacodynamic information, Mouton et al 7 proposed a provisional breakpoint of 4 µg/mL for susceptible Gram-positive microorganisms.…”

Section: In Vitro Antibacterial Activity: Ceftobiprole and The Penicimentioning

confidence: 99%

“…5 Ceftobiprole exhibits potent binding to PBPs from Gram-positive bacteria, including those with decreased beta-lactam sensitivity, such as PBP2a in MRSA (unlike ceftriaxone and ceftazidime), and PBP2x (the primary cephalosporin targets) in penicillin-resistant Streptococcus pneumoniae (ceftobiprole had an eight fold-higher binding affinity for a mutated PBP2x than ceftriaxone). 6 In Escherichia coli, ceftobiprole exhibits strong binding to PBP2 and PBP3 (the primary targets for monobactams and most cephalosporins). Ceftobiprole exhibits a binding profile similar to those of cefepime and ceftazidime in Pseudomonas aeruginosa but with an enhanced binding to PBP2.…”

Section: In Vitro Antibacterial Activity: Ceftobiprole and The Penicimentioning

confidence: 99%

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Emerging agents to combat complicated and resistant infections: focus on ceftobiprole

Bustos

Pozo²

2010

IDR

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Antimicrobial resistance is a global concern. Over the past few years, considerable efforts and resources have been expended to detect, monitor, and understand at the basic level the many different facets of emerging and increasing resistance. Development of new antimicrobial agents has been matched by the development of new mechanisms of resistance by bacteria. Current antibiotics act at a variety of sites within the target bacteria, including the cross-linking enzymes in the cell wall, various ribosomal enzymes, nucleic acid polymerases, and folate synthesis. Ceftobiprole is a novel parenteral cephalosporin with high affinity for most penicillin-binding proteins, including the mecA product penicillin-binding protein 2a, rendering it active against methicillin-resistant staphylococci. Its in vitro activity against staphylococci and multiresistant pneumococci, combined with its Gram-negative spectrum comparable to that of other extended-spectrum cephalosporins, its stability against a wide range of beta-lactamases, and its pharmacokinetic and safety profiles make ceftobiprole an attractive and well tolerated new antimicrobial agent. The US Food and Drug Administration granted ceftobiprole medocaril fast-track status in 2003 for the treatment of complicated skin infections and skin structure infections due to methicillin-resistant staphylococci, and subsequently extended this to treatment of hospital-acquired pneumonia, including ventilator-associated pneumonia due to suspected or proven methicillin-resistant Staphylococcus aureus.

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“…However, drug molecules with TPSA values of 140 Å or higher are expected to have very low absorption [26]. Lipophilicity (miLogP) and TPSA values are essential factors for the prediction of oral bioavailability of drugs [29]. Molinspiration cheminformatics are available from http://www.molinspiration.com.…”

Section: Molinspiration Calculationsmentioning

confidence: 99%

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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Binding of Ceftobiprole and Comparators to the Penicillin-Binding Proteins of Escherichia coli , Pseudomonas aeruginosa , Staphylococcus aureus , and Streptococcus pneumoniae

Cited by 150 publications

References 28 publications

Restoration of Susceptibility of Methicillin-resistant Staphylococcus aureus to β-Lactam Antibiotics by Acidic pH

Restoration of Susceptibility of Methicillin-resistant Staphylococcus aureus to β-Lactam Antibiotics by Acidic pH

Emerging agents to combat complicated and resistant infections: focus on ceftobiprole

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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