Pbp3 antipseudomonals
aeruginosa and related Gram-negative bacteria are sought and our study provides templates to assist that process and allows us to discuss new ways of inhibiting PBPs. B-lactams that inhibit cell wall synthesis by inhibition of peptidoglycan cross-linking. Improved drugs to combat infections by P. aeruginosa is an important human pathogen, the structural data reveal the mode of action of the frontline antibiotic ceftazidime at the molecular level. Most notably, the 6-methoxy group disrupts a high-quality hydrogen bond with a conserved residue important for ligand binding while also being inserted into a crowded active site, possibly destabilizing the active site and. The conserved binding mode of β-lactam-based inhibitors appears to extend to other PBPs, as suggested by a comparison of the PBP3/ceftazidime complex and the Escherichia coli PBP1b/ceftoxamine complex. Complex crystal structures with PBP3 reveal similar binding modes of the two drugs but with important differences. Table 1 summarizes the characteristics of resistance development for the main antipseudomonals, including: a) main mechanisms of resistance developed through exposure to each antibiotic, b) the relatively frequency of spontaneous occurrence, c) the baseline minimal inhibitory concentrations (MICs) and MPCs, and d) development of cross. to that of ceftazidime (PBP3 inhibitor) and imipenem (PBP2 inhibitor). Monobactam, resistant to B-lactamases, inhibits cell wall synthesis by binding to PBP3, synergistic with. 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). CXA-101, previously designated FR264205, is a new antipseudomonal cephalosporin. The orientations of the two β-lactams in the active site and the key interactions formed between the ligands and PBP3 are similar despite differences in the two drugs, indicating a degree of flexibility in the binding site. CXA-101, previously designated FR264205, is a new antipseudomonal cephalosporin. Binding of either carbenicillin or ceftazidime to purified PBP3 increases the thermostability of the enzyme significantly and is associated with local conformational changes, which lead to a narrowing of the substrate-binding cleft. CXA-101 was found to be a potent PBP3 inhibitor and showed affinities > or 2-fold higher than those of ceftazidime for all of the essential PBPs (1b, 1c, 2, and 3).
Overall, the structures of apo and acyl complexes are very similar however, variations in the orientation of the amino-terminal membrane-proximal domain relative to that of the carboxy-terminal transpeptidase domain indicate interdomain flexibility. We report the first crystal structures of a penicillin-binding protein (PBP), PBP3, from Pseudomonas aeruginosa in native form and covalently linked to two important β-lactam antibiotics, carbenicillin and ceftazidime.