7L8O
OXA-48 bound by Compound 4.3
Summary for 7L8O
| Entry DOI | 10.2210/pdb7l8o/pdb |
| Descriptor | Beta-lactamase, 1,2-ETHANEDIOL, 9H-fluorene-2,7-disulfonate, ... (6 entities in total) |
| Functional Keywords | beta-lactamase, carbapenemase, beta-lactamase inhibitor, complex, oxacillinase, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Klebsiella pneumoniae |
| Total number of polymer chains | 4 |
| Total formula weight | 115189.29 |
| Authors | Taylor, D.M.,Hu, L.,Prasad, B.V.V.,Palzkill, T. (deposition date: 2020-12-31, release date: 2021-12-01, Last modification date: 2023-11-15) |
| Primary citation | Taylor, D.M.,Anglin, J.,Hu, L.,Wang, L.,Sankaran, B.,Wang, J.,Matzuk, M.M.,Prasad, B.V.V.,Palzkill, T. Unique Diacidic Fragments Inhibit the OXA-48 Carbapenemase and Enhance the Killing of Escherichia coli Producing OXA-48. Acs Infect Dis., 7:3345-3354, 2021 Cited by PubMed Abstract: Despite the advances in β-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 infections and is not susceptible to most available β-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 β-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 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 . 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. PubMed: 34817169DOI: 10.1021/acsinfecdis.1c00501 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
Download full validation report
