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In this study, we characterized the inhibition by diazabicyclooctanes of penicillin-binding proteins PBP2 and PBP3 from Pseudomonas aeruginosa using protein crystallography and biophysical analyses. Diazabicyclooctane inhibitors such as zidebactam possess this potential as they readily inactivate penicillin-binding proteins, yet cannot be degraded by β-lactamases. Developing novel antibiotics that overcome known resistance mechanisms is highly desired. IMPORTANCE Antibiotic resistance is a significant clinical problem. These molecular insights into the dual-target DBOs advance our knowledge regarding further DBO optimization efforts to develop novel potent β-lactamase-resistant, non-β-lactam PBP inhibitors. Overall, the studies provide insights into zidebactam and WCK 5153 inhibition of PBP2 compared to their inhibition of PBP3 and the evolutionarily related KPC-2 β-lactamase. Even though the DBOs show covalent binding to PBP3, they destabilized PBP3. aeruginosa PBP3 was explored crystallographically. To aid in the design of DBOs that can inhibit multiple PBPs, the ability of three DBOs to interact with P. Both DBOs increase the melting temperature of PBP2, affirming their stabilizing interactions. Modeling of zidebactam in the active site of PBP2 reveals a similar binding mode. The structure suggests a significant role for the diacylhydrazide moiety of WCK 5153 in interacting with the aspartate in the S-X-N/D PBP motif. WCK 5153 forms an inhibitory covalent bond with the catalytic S327 of PBP2. aeruginosa PBP2 in complex with WCK 5153. aeruginosa PBP2 is less susceptible to inhibition by β-lactam antibiotics compared to the Escherichia coli PBP2, we determined the crystal structure of P. To structurally probe their mode of PBP2 inhibition as well as investigate why P. The diazabicyclooctane (DBO) compounds zidebactam and WCK 5153, recognized as β-lactam "enhancers" due to inhibition of Pseudomonas aeruginosa penicillin-binding protein 2 (PBP2), are also class A and C β-lactamase inhibitors. A major mechanism of resistance expressed by MDR pathogens is β-lactamase-mediated degradation of β-lactam antibiotics.
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Multidrug-resistant (MDR) pathogens pose a significant public health threat.