Investigating the promiscuity of the chloramphenicol nitroreductase from Haemophilus influenzae towards the reduction of 4-nitrobenzene derivatives

Keith D. Green, Marina Y. Fosso, Abdelrahman S. Mayhoub, Sylvie Garneau-Tsodikova

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Chloramphenicol nitroreductase (CNR), a drug-modifying enzyme from Haemophilus influenzae, has been shown to be responsible for the conversion of the nitro group into an amine in the antibiotic chloramphenicol (CAM). Since CAM structurally bears a 4-nitrobenzene moiety, we explored the substrate promiscuity of CNR by investigating its nitroreduction of 4-nitrobenzyl derivatives. We tested twenty compounds containing a nitrobenzene core, two nitropyridines, one compound with a vinylogous nitro group, and two aliphatic nitro compounds. In addition, we also synthesized twenty-eight 4-nitrobenzyl derivatives with ether, ester, and thioether substituents and assessed the relative activity of CNR in their presence. We found several of these compounds to be modified by CNR, with the enzyme activity ranging from 1 to 150% when compared to CAM. This data provides insights into two areas: (i) chemoenzymatic reduction of select compounds to avoid harsh chemicals and heavy metals routinely used in reductions of nitro groups and (ii) functional groups that would aid CAM in overcoming the activity of this enzyme.

Original languageEnglish
Pages (from-to)1127-1132
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number9
DOIs
StatePublished - May 1 2019

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Ltd

Keywords

  • Antibiotic
  • Bacterial enzyme
  • Chemoenzymatic deprotection
  • Drug-modifying enzyme
  • Nitroreduction

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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