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

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 beta-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 mu gml(-1). When quinuclidine 1 was combined with beta-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.