4s2p
From Proteopedia
Crystal structure of unbound OXA-48
Structural highlights
FunctionBLO48_KLEPN Class D beta-lactamase which confers resistance to the beta-lactam antibiotics, including amoxicillin, and moderate resistance to cephalosporins and carbapenems such as cephalothin and imipenem; in the DH10B strain of E.coli (PubMed:14693513). Acts via hydrolysis of the beta-lactam ring (PubMed:14693513, PubMed:19477418, PubMed:27073009, PubMed:38161376). Has oxacillin-, cephalothin- and imipenem-hydrolyzing activities (PubMed:14693513, PubMed:19477418, PubMed:27073009, PubMed:38161376).[1] [2] [3] [4] Publication Abstract from PubMedEmerging 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-A-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. Molecular Mechanism of Avibactam-Mediated beta-Lactamase Inhibition.,King DT, King AM, Lal SM, Wright GD, Strynadka NC ACS Infect Dis. 2015 Apr 10;1(4):175-84. doi: 10.1021/acsinfecdis.5b00007. Epub, 2015 Feb 11. PMID:27622530[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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