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

Doris Mia Taylor, Justin Anglin, Suhyeorn Park, Melek N. Ucisik, John C. Faver, Nicholas Simmons, Zhuang Jin, Murugesan Palaniappan, Pranavanand Nyshadham, Feng Li, James Campbell, Liya Hu, Banumathi Sankaran, B. V.Venkataram Prasad, Hongbing Huang, Martin M. Matzuk, Timothy Palzkill

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1214-1227
Number of pages14
JournalACS Infectious Diseases
Volume6
Issue number5
DOIs
StatePublished - May 8 2020
Externally publishedYes

Keywords

  • carbapenemase
  • DEC-Tec
  • DECL
  • DNA-encoded library
  • drug discovery
  • OXA-48
  • β-lactam antibiotic
  • β-lactamase

ASJC Scopus subject areas

  • Infectious Diseases

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