7k5v | pdb_00007k5v

OXA-48 bound by Compound 3.1

spinqualitylabelsall models 7k5v, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7k5v is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BIH, CL, EDO, NA NonStd Res: KCX Activity: Beta-lactamase, with EC number 3.5.2.6 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Despite the advances in beta-lactamase inhibitor development, limited options exist for the class D carbapenemase known as OXA-48. OXA-48 is one of the most prevalent carbapenemases in carbapenem-resistant Enterobacteriaceae infections and is not susceptible to most available beta-lactamase inhibitors. Here, we screened various low-molecular-weight compounds (fragments) against OXA-48 to identify functional scaffolds for inhibitor development. Several biphenyl-, naphthalene-, fluorene-, anthraquinone-, and azobenzene-based compounds were found to inhibit OXA-48 with low micromolar potency despite their small size. Co-crystal structures of OXA-48 with several of these compounds revealed key interactions with the carboxylate-binding pocket, Arg214, and various hydrophobic residues of beta-lactamase that can be exploited in future inhibitor development. A number of the low-micromolar-potency inhibitors, across different scaffolds, synergize with ampicillin to kill Escherichia coli expressing OXA-48, albeit at high concentrations of the respective inhibitors. Additionally, several compounds demonstrated micromolar potency toward the OXA-24 and OXA-58 class D carbapenemases that are prevalent in Acinetobacter baumannii. This work provides foundational information on a variety of chemical scaffolds that can guide the design of effective OXA-48 inhibitors that maintain efficacy as well as potency toward other major class D carbapenemases. Unique Diacidic Fragments Inhibit the OXA-48 Carbapenemase and Enhance the Killing of Escherichia coli Producing OXA-48.,Taylor DM, Anglin J, Hu L, Wang L, Sankaran B, Wang J, Matzuk MM, Prasad BVV, Palzkill T ACS Infect Dis. 2021 Nov 24. doi: 10.1021/acsinfecdis.1c00501. PMID:34817169 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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