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

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 - 13 Jul 2018

Keywords

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

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