8vep | pdb_00008vep
Crystal structure of transpeptidase domain of PBP2 from Neisseria gonorrhoeae cephalosporin-resistant strain H041 acylated by piperacillin
Structural highlights
FunctionF2Z7K9_NEIGO Catalyzes cross-linking of the peptidoglycan cell wall at the division septum.[HAMAP-Rule:MF_02080] Publication Abstract from PubMedEffective treatment of gonorrhea is threatened by the increasing prevalence of Neisseria gonorrhoeae strains resistant to the extended-spectrum cephalosporins (ESCs). Recently, we demonstrated the promise of the third-generation cephalosporin cefoperazone as an antigonococcal agent due to its rapid second-order rate of acylation against penicillin-binding protein 2 (PBP2) from the ESC-resistant strain H041 and robust antimicrobial activity against H041. Noting the presence of a ureido moiety in cefoperazone, we evaluated a subset of structurally similar ureido beta-lactams, including piperacillin, azlocillin, and mezlocillin, for activity against PBP2 from H041 using biochemical and structural analyses. We found that the ureidopenicillin piperacillin has a second-order rate of acylation against PBP2 that is 12-fold higher than cefoperazone and 85-fold higher than ceftriaxone and a lower MIC against H041 than ceftriaxone. Surprisingly, the affinity of ureidopenicillins for PBP2 is minimal, indicating that their inhibitory potency is due to a higher rate of the acylation step of the reaction compared to cephalosporins. Enhanced acylation results from the combination of a penam scaffold with a 2,3-dioxopiperazine-containing R(1) group. Crystal structures show that the ureido beta-lactams overcome the effects of resistance mutations present in PBP2 from H041 by eliciting conformational changes that are hindered when PBP2 interacts with the weaker inhibitor ceftriaxone. Overall, our results support the potential of piperacillin as a treatment for gonorrhea and provide a framework for the future design of beta-lactams with improved activity against ESC-resistant N. gonorrhoeae. Ureidopenicillins Are Potent Inhibitors of Penicillin-Binding Protein 2 from Multidrug-Resistant Neisseria gonorrhoeae H041.,Turner JM, Stratton CM, Bala S, Cardenas Alvarez M, Nicholas RA, Davies C ACS Infect Dis. 2024 Apr 12;10(4):1298-1311. doi: 10.1021/acsinfecdis.3c00713. , Epub 2024 Mar 6. PMID:38446051[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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