8VEQ

Crystal structure of transpeptidase domain of PBP2 from Neisseria gonorrhoeae cephalosporin-resistant strain H041 in complex with azlocillin

8VEQ の概要

• エントリーDOI: 10.2210/pdb8veq/pdb
• 分子名称: Probable peptidoglycan D,D-transpeptidase PenA, (2R,4S)-5,5-dimethyl-2-[(1R)-2-oxo-1-{[(2R)-2-{[(2-oxoimidazolidin-1-yl)carbonyl]amino}-2-phenylacetyl]amino}ethyl]-1,3-thiazolidine-4-carboxylic acid (3 entities in total)
• 機能のキーワード: penicillin-binding protein, transpeptidase, complex, hydrolase
• 由来する生物種: Neisseria gonorrhoeae
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35825.00

構造登録者

Stratton, C.,Bala, S.,Davies, C. (登録日: 2023-12-20, 公開日: 2024-03-20, 最終更新日: 2024-12-25)

主引用文献

Turner, J.M.,Stratton, C.M.,Bala, S.,Cardenas Alvarez, M.,Nicholas, R.A.,Davies, C.
Ureidopenicillins Are Potent Inhibitors of Penicillin-Binding Protein 2 from Multidrug-Resistant Neisseria gonorrhoeae H041.
Acs Infect Dis., 10:1298-1311, 2024

PubMed Abstract: Effective treatment of gonorrhea is threatened by the increasing prevalence of 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 β-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 group. Crystal structures show that the ureido β-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 β-lactams with improved activity against ESC-resistant .

PubMed: 38446051
DOI: 10.1021/acsinfecdis.3c00713

実験手法

X-RAY DIFFRACTION (2.4 Å)