Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria: Structure-activity relationships and mode of action studies

Domiziana Masci, Charlotte Hind, Mohammad K. Islam, Anita Toscani, Melanie Clifford, Antonio Coluccia, Irene Conforti, Meir Touitou, Siham Memdouh, Xumin Wei, Giuseppe La Regina, Romano Silvestri, J. Mark Sutton, Daniele Castagnolo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram + ve and Gram-ve pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.

Original languageEnglish
Pages (from-to)500-514
Number of pages15
JournalEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume178
Early online date3 Jun 2019
DOIs
Publication statusE-pub ahead of print - 3 Jun 2019

Keywords

  • Antimicrobial resistance
  • DNA gyrase
  • Drug resistance
  • ESKAPE bacteria
  • Pyrrole

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