1404289-47-9Relevant academic research and scientific papers
A bactericidal guanidinomethyl biaryl that alters the dynamics of bacterial FtsZ polymerization
Kaul, Malvika,Parhi, Ajit K.,Zhang, Yongzheng,Lavoie, Edmond J.,Tuske, Steve,Arnold, Eddy,Kerrigan, John E.,Pilch, Daniel S.
, p. 10160 - 10176 (2013/01/16)
The prevalence of multidrug resistance among clinically significant bacterial pathogens underscores a critical need for the development of new classes of antibiotics with novel mechanisms of action. Here we describe the synthesis and evaluation of a guanidinomethyl biaryl compound {1-((4′-(tert-butyl)-[1,1′-biphenyl]-3-yl)methyl)guanidine} that targets the bacterial cell division protein FtsZ. In vitro studies with various bacterial FtsZ proteins reveal that the compound alters the dynamics of FtsZ self-polymerization via a stimulatory mechanism, while minimally impacting the polymerization of tubulin, the closest mammalian homologue of FtsZ. The FtsZ binding site of the compound is identified through a combination of computational and mutational approaches. The compound exhibits a broad spectrum of bactericidal activity, including activity against the multidrug-resistant pathogens methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), while also exhibiting a minimal potential to induce resistance. Taken together, our results highlight the compound as a promising new FtsZ-targeting bactericidal agent.
