WCK 5222 (cefepime/zidebactam) is under clinical development for the treatment of serious Gram-negative infections. 9 There is an urgent need to develop comprehensively effective therapies for MBL-producing Enterobacterales and P.
7, 8 Cefepime/taniborbactam is not active against IMP-expressing isolates and MBL-expressing P. The aztreonam/avibactam combination does not cover MBL-expressing P. Β-Lactam/β-lactamase inhibitor combinations targeting MBL-expressing pathogens are marred with spectrum gaps. 1, 2 The current evolving resistance scenario poses therapeutic challenges to available and pipeline β-lactam-based therapies. 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.CDC reports carbapenem-resistant Enterobacterales and MDR Acinetobacter baumannii as urgent threats and Pseudomonas aeruginosa as a serious threat. 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. 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. 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. 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. 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.
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