A bactericidal guanidinomethyl biaryl that alters the dynamics of bacterial FtsZ polymerization.
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.
Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School , Piscataway, New Jersey 08854-5635, USA.
Malvika
M
Kaul
Ajit K
AK
Parhi
Yongzheng
Y
Zhang
Edmond J
EJ
LaVoie
Steve
S
Tuske
Eddy
E
Arnold
John E
JE
Kerrigan
Daniel S
DS
Pilch
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D016983:Enterococcus / Q000187:drug effects*; D006146:Guanidines / Q000138:chemical synthesis / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D058105:Polymerization / Q000187:drug effects*; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D020713:Vancomycin Resistance / Q000187:drug effects*
C577958:1-((4'-(tert-butyl)-(1,1'-biphenyl)-3-yl)methyl)guanidine; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001713:Biphenyl Compounds; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D006146:Guanidines