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Screening and Design of Inhibitor Scaffolds for the Antibiotic Resistance Oxacillinase-48 (OXA-48) through Surface Plasmon Resonance Screening.

Lund BA, Christopeit T, Guttormsen Y, Bayer A, Leiros HK
J Med Chem 59 5542-54 (2016)
Related entries: 5dtk, 5dtt, 5dva

Cited: 12 times
EuropePMC logo PMID: 27165692

Abstract

The spread of antibiotic resistant bacteria is a global threat that shakes the foundations of modern healthcare. β-Lactamases are enzymes that confer resistance to β-lactam antibiotics in bacteria, and there is a critical need for new inhibitors of these enzymes for combination therapy together with an antibiotic. With this in mind, we have screened a library of 490 fragments to identify starting points for the development of new inhibitors of the class D β-lactamase oxacillinase-48 (OXA-48) through surface plasmon resonance (SPR), dose-rate inhibition assays, and X-ray crystallography. Furthermore, we have uncovered structure-activity relationships and used alternate conformations from a crystallographic structure to grow a fragment into a more potent compound with a KD of 50 μM and an IC50 of 18 μM.

Reviews citing this publication (1)

  1. A review on the mechanistic details of OXA enzymes of ESKAPE pathogens. Avci FG, Tastekil I, Jaisi A, Ozbek Sarica P, Sariyar Akbulut B. Pathog Glob Health 117 219-234 (2023)

Articles citing this publication (11)

  1. OXA-48-Mediated Ceftazidime-Avibactam Resistance Is Associated with Evolutionary Trade-Offs. Fröhlich C, Sørum V, Thomassen AM, Johnsen PJ, Leiros HS, Samuelsen Ø. mSphere 4 e00024-19 (2019)
  2. Identifying Oxacillinase-48 Carbapenemase Inhibitors Using DNA-Encoded Chemical Libraries. Taylor DM, Anglin J, Park S, Ucisik MN, Faver JC, Simmons N, Jin Z, Palaniappan M, Nyshadham P, Li F, Campbell J, Hu L, Sankaran B, Prasad BVV, Huang H, Matzuk MM, Palzkill T. ACS Infect Dis 6 1214-1227 (2020)
  3. Cryptic β-Lactamase Evolution Is Driven by Low β-Lactam Concentrations. Fröhlich C, Gama JA, Harms K, Hirvonen VHA, Lund BA, van der Kamp MW, Johnsen PJ, Samuelsen Ø, Leiros HS. mSphere 6 e00108-21 (2021)
  4. Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond. Ai Y, Hwang L, MacKerell AD, Melnick A, Xue F. J Med Chem 64 4333-4358 (2021)
  5. The biological assembly of OXA-48 reveals a dimer interface with high charge complementarity and very high affinity. Lund BA, Thomassen AM, Nesheim BHB, Carlsen TJO, Isaksson J, Christopeit T, Leiros HS. FEBS J 285 4214-4228 (2018)
  6. Label-Free Visualization of Carbapenemase Activity in Living Bacteria. Zhang Y, Lei JE, He Y, Yang J, Wang W, Wasey A, Xu J, Lin Y, Fan H, Jing G, Zhang C, Jin Y. Angew Chem Int Ed Engl 57 17120-17124 (2018)
  7. Biochemical and biophysical characterization of the OXA-48-like carbapenemase OXA-436. Lund BA, Thomassen AM, Carlsen TJW, Leiros HKS. Acta Crystallogr F Struct Biol Commun 77 312-318 (2021)
  8. Discovery of Novel Chemical Series of OXA-48 β-Lactamase Inhibitors by High-Throughput Screening. Garofalo B, Prati F, Buonfiglio R, Coletta I, D'Atanasio N, Molteni A, Carettoni D, Wanke V, Pochetti G, Montanari R, Capelli D, Milanese C, Di Giorgio FP, Ombrato R. Pharmaceuticals (Basel) 14 612 (2021)
  9. Revisiting the hydrolysis of ampicillin catalyzed by Temoneira-1 β-lactamase, and the effect of Ni(II), Cd(II) and Hg(II). Nafaee ZH, Egyed V, Jancsó A, Tóth A, Gerami AM, Dang TT, Heiniger-Schell J, Hemmingsen L, Hunyadi-Gulyás É, Peintler G, Gyurcsik B. Protein Sci 32 e4809 (2023)
  10. 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 7 3345-3354 (2021)
  11. OXA-66 structure and oligomerisation of OXAAb enzymes. Takebayashi Y, Henderson SR, Chirgadze DY, Warburton PJ, Evans BA. Access Microbiol 4 acmi000412 (2022)


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