Antimicrobial activity of a quinuclidine-based FtsZ inhibitor and its synergistic potential with β-lactam antibiotics

Fung Yi Chan, Ning Sun, Yun Chung Leung, Kwok Yin Wong

Research output: Journal article publicationJournal articleAcademic researchpeer-review

31 Citations (Scopus)

Abstract

Filamenting temperature-sensitive mutant Z (FtsZ) is an essential cell division protein that cooperates in the formation of the cytokinetic Z-ring in most bacteria and has thus been recognized as a promising antimicrobial drug target. We have recently used a structure-based virtual screening approach to identify pyrimidine-linked quinuclidines as a novel class of FtsZ inhibitors. In this study, we further investigated the antibacterial properties of one of the most potent compounds (quinuclidine 1) and its synergistic activity with β-lactam antibiotics. Susceptibility results showed that quinuclidine 1 was active against multiple antibiotic-resistant bacterial strains including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium with minimal inhibitory concentrations of 24 μg ml-1. When quinuclidine 1 was combined with β-lactam antibiotics, synergistic antimicrobial activities against antibiotic-resistant strains of S. aureus were found. Further in vitro studies suggest that prevention of FtsZ protofilament formation by quinuclidine 1 impairs the formation of Z-ring, and thus inhibits bacterial division. These findings open a new approach for development of quinuclidine-based FtsZ inhibitors into potent antimicrobial agents.
Original languageEnglish
Pages (from-to)253-258
Number of pages6
JournalJournal of Antibiotics
Volume68
Issue number4
DOIs
Publication statusPublished - 30 Apr 2015

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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