scholarly journals Affinity of the New Cephalosporin CXA-101 to Penicillin-Binding Proteins of Pseudomonas aeruginosa

2010 ◽  
Vol 54 (9) ◽  
pp. 3933-3937 ◽  
Author(s):  
Bartolomé Moyá ◽  
Laura Zamorano ◽  
Carlos Juan ◽  
Yigong Ge ◽  
Antonio Oliver
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Bactericidal Activity ◽  
Cell Morphology ◽  
Binding Proteins ◽  
Bacterial Load ◽  
Penicillin Binding Protein ◽  
Lower Affinity ◽  
Penicillin Binding Proteins ◽  
Log Reduction ◽  
High Affinity

ABSTRACT CXA-101, previously designated FR264205, is a new antipseudomonal cephalosporin. The objective of this study was to determine the penicillin-binding protein (PBP) inhibition profile of CXA-101 compared to that of ceftazidime (PBP3 inhibitor) and imipenem (PBP2 inhibitor). Killing kinetics, the induction of AmpC expression, and associated changes on cell morphology were also investigated. The MICs for CXA-101, ceftazidime, and imipenem were 0.5, 1, and 1 μg/ml, respectively. Killing curves revealed that CXA-101 shows a concentration-independent bactericidal activity, with concentrations of 1× the MIC (0.5 μg/ml) producing a >3-log reduction in bacterial load after 8 h of incubation. Live-dead staining showed that concentrations of CXA-101 as low as 0.5× the MIC stopped bacterial septation and induced an intense filamentation, which is consistent with the documented high affinity of PBP3. CXA-101 was found to be a potent PBP3 inhibitor and showed affinities ≥2-fold higher than those of ceftazidime for all of the essential PBPs (1b, 1c, 2, and 3). Compared to imipenem, in addition to the obvious inverse PBP2/PBP3 affinities, CXA-101 showed a significantly higher affinity for PBP1b but a lower affinity for PBP1c. Furthermore, CXA-101, like ceftazidime and in contrast to imipenem, was found to be a very weak inducer of AmpC expression, consistent with the low PBP4 affinity documented.

scholarly journals Affinity of Tomopenem (CS-023) for Penicillin-Binding Proteins in Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa

2008 ◽  
Vol 53 (3) ◽  
pp. 1238-1241 ◽  
Author(s):  
Tetsufumi Koga ◽  
Chika Sugihara ◽  
Masayo Kakuta ◽  
Nobuhisa Masuda ◽  
Eiko Namba ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Binding Proteins ◽  
Binding Protein ◽  
Penicillin Binding Protein ◽  
Penicillin Binding Proteins ◽  
E Coli ◽  
High Affinity

ABSTRACT Tomopenem (formerly CS-023), a novel 1β-methylcarbapenem, exhibited high affinity for penicillin-binding protein (PBP) 2 in Staphylococcus aureus, PBP 2 in Escherichia coli, and PBPs 2 and 3 in Pseudomonas aeruginosa, which are considered major lethal targets. Morphologically, tomopenem induced spherical forms in E. coli and short filamentation with bulges in P. aeruginosa, which correlated with the drug's PBP profiles. The potential of resistance of these bacteria to tomopenem was comparable to that to imipenem.

scholarly journals Affinity of Doripenem and Comparators to Penicillin-Binding Proteins in Escherichia coli and Pseudomonas aeruginosa

2008 ◽  
Vol 52 (4) ◽  
pp. 1510-1512 ◽  
Author(s):  
Todd A. Davies ◽  
Wenchi Shang ◽  
Karen Bush ◽  
Robert K. Flamm
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Cell Death ◽  
Broad Spectrum ◽  
Binding Proteins ◽  
Penicillin Binding Protein ◽  
Gram Negative ◽  
Penicillin Binding Proteins ◽  
High Affinity ◽  
Affinity Profile

ABSTRACT Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.

scholarly journals Increasing Ceftriaxone Resistance and Multiple Alterations of Penicillin-Binding Proteins among Penicillin-Resistant Streptococcus pneumoniae Isolates in Taiwan

2007 ◽  
Vol 51 (9) ◽  
pp. 3404-3406 ◽  
Author(s):  
Cheng-Hsun Chiu ◽  
Lin-Hui Su ◽  
Yhu-Chering Huang ◽  
Jui-Chia Lai ◽  
Hsiu-Ling Chen ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Amino Acid ◽  
Binding Proteins ◽  
Binding Protein ◽  
Penicillin Binding Protein ◽  
Penicillin Binding Proteins

ABSTRACT The rate of nonsusceptibility of penicillin-resistant Streptococcus pneumoniae strains to ceftriaxone increased significantly in Taiwan in 2005. Approximately 90% of the ceftriaxone-nonsusceptible isolates were found to be of four major serotypes (serotypes 6B, 14, 19F, and 23F). Seven amino acid alterations in the penicillin-binding protein 2B transpeptidase-encoding region specifically contributed to the resistance.

scholarly journals Penicillin-binding proteins and carboxypeptidase/transpeptidase activities in Proteus vulgaris P18 and its penicillin-induced stable L-forms

1982 ◽  
Vol 152 (3) ◽  
pp. 1042-1048
Author(s):  
A Rousset ◽  
M Nguyen-Distèche ◽  
R Minck ◽  
J M Ghuysen
Keyword(s):  
Plasma Membrane ◽  
Binding Proteins ◽  
Binding Protein ◽  
Penicillin Binding Protein ◽  
Proteus Vulgaris ◽  
Penicillin Binding Proteins

The originally penicillin-induced, wall-less stable L-forms of Proteus vulgaris P18, isolated by Tulasne in 1949 and since then cultured in he absence of penicillin, have kept the ability to synthesize the seven penicillin-binding proteins and the various DD- and LD-peptidase activities found in the parental bacteria and known to be involved in wall peptidoglycan metabolism. The stable L-forms, however, secrete during growth both the highly penicillin-sensitive, DD-carboxy-peptidase-transpeptidase penicillin-binding protein PBP4 (which in normal bacteria is relatively loosely bound to the plasma membrane) and the penicillin-insensitive LD-carboxypeptidase (which in normal bacteria is located in the periplasmic region).

scholarly journals bla ROB-1 Presence on pB1000 in Haemophilus influenzae Is Widespread, and Variable Cefaclor Resistance Is Associated with Altered Penicillin-Binding Proteins

2010 ◽  
Vol 54 (11) ◽  
pp. 4945-4947 ◽  
Author(s):  
Stephen G. Tristram ◽  
Rachael Littlejohn ◽  
Richard S. Bradbury
Keyword(s):  
Haemophilus Influenzae ◽  
North American ◽  
Binding Proteins ◽  
Binding Protein ◽  
Low Frequency ◽  
Penicillin Binding Protein ◽  
Penicillin Binding Proteins

ABSTRACT Plasmid pB1000 is a small replicon recently identified as bearing bla ROB-1 in animal and human Pasteurellaceae in Spain. We identified pB1000 in 11 bla ROB-1-positive Australian and North American Haemophilus influenzae isolates, suggesting a wider role for pB1000 in disseminating bla ROB-1. Native H. influenzae conjugative elements can mobilize plasmids similar to pB1000 at a low frequency of 10−8, and this might account for the infrequency of bla ROB-1 compared to the rate of occurrence of bla TEM-1. Altered penicillin-binding protein 3 was associated with an increased cefaclor MIC in 3 isolates.

scholarly journals β-lactam Resistance in Pseudomonas aeruginosa: Current Status, Future Prospects

Pathogens ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1638
Author(s):  
Karl A. Glen ◽  
Iain L. Lamont
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Cell Division ◽  
Biofilm Formation ◽  
Opportunistic Pathogen ◽  
Current Status ◽  
Future Prospects ◽  
Penicillin Binding Protein ◽  
Chronic Infections ◽  
Penicillin Binding Proteins ◽  
Wide Range

Pseudomonas aeruginosa is a major opportunistic pathogen, causing a wide range of acute and chronic infections. β-lactam antibiotics including penicillins, carbapenems, monobactams, and cephalosporins play a key role in the treatment of P. aeruginosa infections. However, a significant number of isolates of these bacteria are resistant to β-lactams, complicating treatment of infections and leading to worse outcomes for patients. In this review, we summarize studies demonstrating the health and economic impacts associated with β-lactam-resistant P. aeruginosa. We then describe how β-lactams bind to and inhibit P. aeruginosa penicillin-binding proteins that are required for synthesis and remodelling of peptidoglycan. Resistance to β-lactams is multifactorial and can involve changes to a key target protein, penicillin-binding protein 3, that is essential for cell division; reduced uptake or increased efflux of β-lactams; degradation of β-lactam antibiotics by increased expression or altered substrate specificity of an AmpC β-lactamase, or by the acquisition of β-lactamases through horizontal gene transfer; and changes to biofilm formation and metabolism. The current understanding of these mechanisms is discussed. Lastly, important knowledge gaps are identified, and possible strategies for enhancing the effectiveness of β-lactam antibiotics in treating P. aeruginosa infections are considered.

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