Derivatives of Ribosome-Inhibiting Antibiotic Chloramphenicol Inhibit the Biosynthesis of Bacterial Cell Wall

Sivan Louzoun Zada, Keith D. Green, Sanjib K. Shrestha, Ido M. Herzog, Sylvie Garneau-Tsodikova, Micha Fridman

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Here, we describe the preparation and evaluation of α,β-unsaturated carbonyl derivatives of the bacterial translation inhibiting antibiotic chloramphenicol (CAM). Compared to the parent antibiotic, two compounds containing α,β-unsaturated ketones (1 and 4) displayed a broader spectrum of activity against a panel of Gram-positive pathogens with a minimum inhibitory concentration range of 2-32 μg/mL. Interestingly, unlike the parent CAM, these compounds do not inhibit bacterial translation. Microscopic evidence and metabolic labeling of a cell wall peptidoglycan suggested that compounds 1 and 4 caused extensive damage to the envelope of Staphylococcus aureus cells by inhibition of the early stage of cell wall peptidoglycan biosynthesis. Unlike the effect of membrane-disrupting antimicrobial cationic amphiphiles, these compounds did not rapidly permeabilize the bacterial membrane. Like the parent antibiotic CAM, compounds 1 and 4 had a bacteriostatic effect on S. aureus. Both compounds 1 and 4 were cytotoxic to immortalized nucleated mammalian cells; however, neither caused measurable membrane damage to mammalian red blood cells. These data suggest that the reported CAM-derived antimicrobial agents offer a new molecular scaffold for development of novel bacterial cell wall biosynthesis inhibiting antibiotics.

Original languageEnglish
Pages (from-to)1121-1129
Number of pages9
JournalACS Infectious Diseases
Volume4
Issue number7
DOIs
StatePublished - Jul 13 2018

Bibliographical note

Funding Information:
This work was supported by a BSF grant 2012007 (to S.G.-T. and M.F.), by a National Institutes of Health (NIH) grant AI090048 (to S.G.-T.), by the Israel Science Foundation Grant 6/14 (to M.F.), by the Israel Ministry of Science Technology & Space, Grant 48966 (to M.F.), by the Israel Ministry of Science Technology & Space, Scholarship 3-13550 (to S.L.Z.), and by startup funds from the College of Pharmacy at the University of Kentucky (to S.G.-T.). We thank Mr. Raphael I. Benhamou and Mr. Kfir B. Steinbuch for their help with PI and hemolysis experiments. We thank Dr. Vered Holdengreber for her professional assistance in obtaining transmission electron microscopy images. We thank Prof. Daniel E. Kahne (Harvard University, USA) for the generous gift of the E. coli NR698 strain used for determination of MIC values.

Publisher Copyright:
Copyright © 2018 American Chemical Society.

Keywords

  • antibiotics
  • bacterial resistance
  • cell envelope
  • chloramphenicol
  • in vitro translation

ASJC Scopus subject areas

  • Infectious Diseases

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