期刊
PLOS ONE
卷 10, 期 9, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0136813
关键词
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资金
- AstraZeneca
- Cleveland Department of Veterans Affairs
- Veterans Affairs Career Development Award
- Department of Veterans Affairs Merit Review Program [1I01BX001974]
- Veterans Integrated Service Network 10 Geriatric Research, Education, and Clinical Center (VISN 10 GRECC)
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01 AI100560, R01 AI063517]
beta-Lactamase inhibition is an important clinical strategy in overcoming beta-lactamase-mediated resistance to beta-lactam antibiotics in Gram negative bacteria. A new beta-lactamase inhibitor, avibactam, is entering the clinical arena and promising to be a major step forward in our antibiotic armamentarium. Avibactam has remarkable broad-spectrum activity in being able to inhibit classes A, C, and some class D beta-lactamases. We present here structural investigations into class A beta-lactamase inhibition by avibactam as we report the crystal structures of SHV-1, the chromosomal penicillinase of Klebsiella pneumoniae, and KPC-2, an acquired carbapenemase found in the same pathogen, complexed with avibactam. The 1.80 angstrom KPC-2 and 1.42 angstrom resolution SHV-1 beta-lactamase avibactam complex structures reveal avibactam covalently bonded to the catalytic S70 residue. Analysis of the interactions and chair-shaped conformation of avibactam bound to the active sites of KPC-2 and SHV-1 provides structural insights into recently laboratory-generated amino acid substitutions that result in resistance to avibactam in KPC-2 and SHV-1. Furthermore, we observed several important differences in the interactions with amino acid residues, in particular that avibactam forms hydrogen bonds to S130 in KPC-2 but not in SHV-1, that can possibly explain some of the different kinetic constants of inhibition. Our observations provide a possible reason for the ability of KPC-2 beta-lactamase to slowly desulfate avibactam with a potential role for the stereochemistry around the N1 atom of avibactam and/or the presence of an active site water molecule that could aid in avibactam desulfation, an unexpected consequence of novel inhibition chemistry.
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