ABSTRACT
The antibiotic vancomycin-that binds lipid II in the bacterial cell membrane-was conjugated to a mono- and tetravalent mimic of the tris-histidine catalytic triad of metalloenzymes. Targeted hydrolysis by the conjugate was observed using model membranes containing lipid II, and in vitro MIC-values of the targeted mimic constructs could be modulated by Zn-ions.
Subject(s)
Anti-Bacterial Agents/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Imidazoles/chemistry , Uridine Diphosphate N-Acetylmuramic Acid/analogs & derivatives , Vancomycin/analogs & derivatives , Zinc Sulfate/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Catalysis , Cell Membrane/chemistry , Dendrimers/chemistry , Hydrolysis , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Microbial Sensitivity Tests , Uridine Diphosphate N-Acetylmuramic Acid/chemistry , Vancomycin/chemical synthesis , Vancomycin/chemistry , Vancomycin/pharmacologyABSTRACT
Lipid II is a crucial component in bacterial cell wall synthesis [Breukink, E., et al. (1999) Science 286, 2361-2364]. It is the target of a number of important antibiotics, which include vancomycin and nisin [Breukink, E., and de Kruijff, B. (2006) Nat. Rev. Drug Discovery 5, 321-332]. Here we show that a hybrid antibiotic that consists of vancomycin and nisin fragments is significantly more active than the separate fragments against vancomycin resistant entercocci (VRE). Three different hybrids were synthesized using click chemistry and compared. Optimal spacer lengths and connection points were predicted using computer modeling.
