Interactions of Ceftobiprole with β-Lactamases from Molecular Classes A to D

Queenan, Anne Marie; Shang, Wenchi; Kania, Malgosia; Page, Malcolm G. P.; Bush, Karen

doi:10.1128/aac.00218-07

Cited by 83 publications

(74 citation statements)

References 37 publications

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“…Freeze-thaw lysates of log-phase cultures were tested for ␤-lactamase activity by measuring initial hydrolysis rates with nitrocefin (100 M) as the substrate (26). ␤-Lactamase activity was expressed in micromoles of nitrocefin hydrolyzed per minute per milligram of protein.…”

Section: Methodsmentioning

confidence: 99%

Effect of MexXY Overexpression on Ceftobiprole Susceptibility in Pseudomonas aeruginosa

Baum

Crespo-Carbone

Morrow

et al. 2009

Antimicrob Agents Chemother

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Ceftobiprole, an anti-methicillin-resistant Staphylococcus aureus broad-spectrum cephalosporin, has activity (MIC for 50% of strains tested, <4 g/ml) against many Pseudomonas aeruginosa strains. A common mechanism of P. aeruginosa resistance to ␤-lactams, including cefepime and ceftazidime, is efflux via increased expression of Mex pumps, especially MexAB. MexXY has differential substrate specificity, recognizing cefepime but not ceftazidime. In ceftobiprole clinical studies, paired isolates of P. aeruginosa from four subjects demonstrated ceftobiprole MICs of 2 to 4 g/ml at baseline but 16 g/ml posttreatment, unrelated to ␤-lactamase levels. Within each pair, the level of mexXY RNA, but not mexAB, mexCD, and mexEF, increased by an average of 50-fold from baseline to posttreatment isolates. Sequencing of the negative regulatory gene mexZ indicated that each posttreatment isolate contained a mutation not present at baseline. mexXY expression as a primary ceftobiprole and cefepime resistance mechanism was further examined in isogenic pairs by using cloned mexXY and mexZ. Expression of cloned mexXY in strain PAO1 or in a baseline isolate increased the ceftobiprole MIC to that for the posttreatment isolate. In contrast, in posttreatment isolates, lowering mexXY expression via introduction of cloned mexZ decreased the ceftobiprole MIC to that for the baseline isolates. Similar changes were observed for cefepime. A spontaneous mutant selectively overexpressing mexXY displayed a fourfold elevation in its ceftobiprole MIC, while overexpression of mexAB, -CD, and -EF had a minimal effect. These data indicate that ceftobiprole, like cefepime, is an atypical ␤-lactam that is a substrate for the MexXY efflux pump in P. aeruginosa.Ceftobiprole is a broad-spectrum, anti-methicillin-resistant Staphylococcus aureus cephalosporin with in vitro microbiological activity against many strains of Pseudomonas aeruginosa (MIC for 50% of strains tested, Յ4 g/ml) (4, 22). Resistance to antipseudomonal cephalosporins can be due to overexpression of the chromosomal AmpC cephalosporinase (17); however, decreased susceptibility of P. aeruginosa to a wide variety of antibiotics can also be attributed to drug efflux (17, 21). In particular, basal expression of the Mex pumps of the resistance nodulation division family appears to be responsible for the intrinsic resistance of P. aeruginosa to multiple antibiotics and for enhanced resistance upon overexpression (21, 23). The efflux pumps MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM have each been shown to be clinically relevant factors for decreased antibiotic susceptibility, with expression of the operons encoding these pumps subject to regulation (21). Pump overexpression may be due to an assortment of mutations that affect regulation of transcription from the efflux operon, such as mutations in the cognate repressor or in a global regulatory gene, or upstream of the operon, including but not limited to its promoter (21).The MexAB-OprM efflux pump is constitutively expressed in P. aerugi...

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Section: Methodsmentioning

confidence: 99%

Effect of MexXY Overexpression on Ceftobiprole Susceptibility in Pseudomonas aeruginosa

Baum

Crespo-Carbone

Morrow

et al. 2009

Antimicrob Agents Chemother

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“…This is in contrast to some AmpC-overproducing members of the Enterobacteriaceae, which remain susceptible to cefepime and require additional mechanisms to develop cefepime resistance (i.e., downregulation of porin production) (13,45,78,194,223). Although it is possible that variability in the hydrolytic activity of AmpCs from P. aeruginosa and the Enterobacteriaceae could play a role in these differences, cefepime hydrolysis data obtained with purified AmpC enzymes do not support this hypothesis (208). Rather, the greater impermeability of the P. aeruginosa outer membrane may play an important role in allowing AmpC overproduction to push cefepime MICs above the resistance breakpoint (75).…”

Section: Ampc-mediated Resistancementioning

confidence: 99%

Antibacterial-ResistantPseudomonas aeruginosa: Clinical Impact and Complex Regulation of Chromosomally Encoded Resistance Mechanisms

2009

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SUMMARY Treatment of infectious diseases becomes more challenging with each passing year. This is especially true for infections caused by the opportunistic pathogen Pseudomonas aeruginosa, with its ability to rapidly develop resistance to multiple classes of antibiotics. Although the import of resistance mechanisms on mobile genetic elements is always a concern, the most difficult challenge we face with P. aeruginosa is its ability to rapidly develop resistance during the course of treating an infection. The chromosomally encoded AmpC cephalosporinase, the outer membrane porin OprD, and the multidrug efflux pumps are particularly relevant to this therapeutic challenge. The discussion presented in this review highlights the clinical significance of these chromosomally encoded resistance mechanisms, as well as the complex mechanisms/pathways by which P. aeruginosa regulates their expression. Although a great deal of knowledge has been gained toward understanding the regulation of AmpC, OprD, and efflux pumps in P. aeruginosa, it is clear that we have much to learn about how this resourceful pathogen coregulates different resistance mechanisms to overcome the antibacterial challenges it faces.

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“…ESBLs hydrolyze penicillins, narrow-and extended-spectrum cephalosporins (including the anti-methicillin-resistant S. aureus [MRSA] cephalosporin ceftobiprole), and the monobactam aztreonam (11,321,357). In contrast, ESBLs cannot efficiently degrade cephamycins, carbapenems, and ␤-lactamase inhibitors.…”

Section: Classificationmentioning

confidence: 99%

Three Decades of β-Lactamase Inhibitors

Drawz¹,

2010

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SUMMARYSince the introduction of penicillin, β-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial β-lactamases. β-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clinical practice. These inhibitors greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of seriousEnterobacteriaceaeand penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to β-lactam-β-lactamase inhibitor combinations. Furthermore, the prevalence of clinically relevant β-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of β-lactams. Here, we review the catalytic mechanisms of each β-lactamase class. We then discuss approaches for circumventing β-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clinical and microbiological features of β-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compounds and the chemical features of these agents that may contribute to a “second generation” of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of β-lactamases.

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Interactions of Ceftobiprole with β-Lactamases from Molecular Classes A to D

Cited by 83 publications

References 37 publications

Effect of MexXY Overexpression on Ceftobiprole Susceptibility in Pseudomonas aeruginosa

Effect of MexXY Overexpression on Ceftobiprole Susceptibility in Pseudomonas aeruginosa

Antibacterial-ResistantPseudomonas aeruginosa: Clinical Impact and Complex Regulation of Chromosomally Encoded Resistance Mechanisms

Three Decades of β-Lactamase Inhibitors

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