Identifying Oxacillinase-48 Carbapenemase Inhibitors Using DNA-Encoded Chemical Libraries

ACS Infect Dis. 2020 May 8;6(5):1214-1227. doi: 10.1021/acsinfecdis.0c00015. Epub 2020 Mar 25.


Bacterial resistance to β-lactam antibiotics is largely mediated by β-lactamases, which catalyze the hydrolysis of these drugs and continue to emerge in response to antibiotic use. β-Lactamases that hydrolyze the last resort carbapenem class of β-lactam antibiotics (carbapenemases) are a growing global health threat. Inhibitors have been developed to prevent β-lactamase-mediated hydrolysis and restore the efficacy of these antibiotics. However, there are few inhibitors available for problematic carbapenemases such as oxacillinase-48 (OXA-48). A DNA-encoded chemical library approach was used to rapidly screen for compounds that bind and potentially inhibit OXA-48. Using this approach, a hit compound, CDD-97, was identified with submicromolar potency (Ki = 0.53 ± 0.08 μM) against OXA-48. X-ray crystallography showed that CDD-97 binds noncovalently in the active site of OXA-48. Synthesis and testing of derivatives of CDD-97 revealed structure-activity relationships and informed the design of a compound with a 2-fold increase in potency. CDD-97, however, synergizes poorly with β-lactam antibiotics to inhibit the growth of bacteria expressing OXA-48 due to poor accumulation into E. coli. Despite the low in vivo activity, CDD-97 provides new insights into OXA-48 inhibition and demonstrates the potential of using DNA-encoded chemistry technology to rapidly identify β-lactamase binders and to study β-lactamase inhibition, leading to clinically useful inhibitors.

Keywords: DEC-Tec; DECL; DNA-encoded library; OXA-48; carbapenemase; drug discovery; β-lactam antibiotic; β-lactamase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bacterial Proteins / antagonists & inhibitors*
  • DNA
  • Escherichia coli / drug effects
  • Small Molecule Libraries*
  • beta-Lactamase Inhibitors* / pharmacology
  • beta-Lactamases


  • Bacterial Proteins
  • Small Molecule Libraries
  • beta-Lactamase Inhibitors
  • DNA
  • beta-Lactamases
  • carbapenemase
  • oxacillinase