Non-catalytic-Region Mutations Conferring Transition of Class A β-Lactamases Into ESBLs

Thinh Phat Cao, Hyojeong Yi, Immanuel Dhanasingh, Suparna Ghosh, Jin Myung Choi, Kun Ho Lee, Seol Ryu, Heenam Stanley Kim, Sung Haeng Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Despite class A ESBLs carrying substitutions outside catalytic regions, such as Cys69Tyr or Asn136Asp, have emerged as new clinical threats, the molecular mechanisms underlying their acquired antibiotics-hydrolytic activity remains unclear. We discovered that this non-catalytic-region (NCR) mutations induce significant dislocation of β3-β4 strands, conformational changes in critical residues associated with ligand binding to the lid domain, dynamic fluctuation of Ω-loop and β3-β4 elements. Such structural changes increase catalytic regions’ flexibility, enlarge active site, and thereby accommodate third-generation cephalosporin antibiotics, ceftazidime (CAZ). Notably, the electrostatic property around the oxyanion hole of Cys69Tyr ESBL is significantly changed, resulting in possible additional stabilization of the acyl-enzyme intermediate. Interestingly, the NCR mutations are as effective for antibiotic resistance by altering the structure and dynamics in regions mediating substrate recognition and binding as single amino-acid substitutions in the catalytic region of the canonical ESBLs. We believe that our findings are crucial in developing successful therapeutic strategies against diverse class A ESBLs, including the new NCR-ESBLs.

Original languageEnglish
Article number598998
JournalFrontiers in Molecular Biosciences
Volume7
DOIs
Publication statusPublished - 2020 Nov 27

Keywords

  • X-ray crystallography
  • antibiotic resistance
  • ceftazidime
  • extended-spectrum β-lactamase
  • non-catalytic-region ESBL

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

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