期刊
ACS INFECTIOUS DISEASES
卷 1, 期 4, 页码 175-184出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.5b00007
关键词
beta-Lactamase; avibactam; inhibition
资金
- CIHR [MT-13536]
- HHMI International Scholar Program
- CFI
- BCKDF
- Canada Research Chair Programs
- NSERC grant [237480]
- Canada Research Chair in Antibiotic Biochemistry
Emerging beta-lactamase-mediated resistance is threatening the clinical utility of the single most prominent class of antibacterial agents used in medicine, the beta-lactams. The diazabicyclooctane avibactam is able to inhibit a wider range of serine beta-lactamases than has been previously observed with beta-lactamase inhibitors such as the widely prescribed clavulanic acid. However, despite its broad-spectrum activity, variable levels of inhibition have been observed for molecular class D beta-lactamases. In order to better understand the molecular basis and spectrum of inhibition by avibactam, we provide structural and mechanistic analysis of the compound in complex with important class A and D serine beta-lactamases. Herein, we reveal the 1.7- and 2.0-angstrom-resolution crystal structures of avibactam covalently bound to class D beta-lactamases OXA-10 and OXA-48. Furthermore, a kinetic analysis of key active-site mutants for class A beta-lactamase CTX-M-15 allows us to propose a validated mechanism for avibactam-mediated beta-lactamase inhibition including a unique role for S130, which acts as a general base. This study provides molecular insights that will aid in the design and development of avibactam-based chemotherapeutic agents effective against emerging drug-resistant microorganisms.
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