title: Synthesis, characterization and activity of new phosphonate dipeptides as potential inhibitors of VanX.
abstract: VanX, a Zn(II)-dependent D-ala-D-ala dipeptidase, is essential for vancomycin resistance in Enterococcus faecium. The enzymatic activity of VanX was previously found to be inhibited competitively by 2-{[(1-aminoethyl) (hydroxy) phosphoryl]oxy} propanoic acid (1B). Here we report the synthesis and characterization of seven phosphonate dipeptide analogs of D-ala-D-ala with various substituent, the activity evaluation indicated that six of these phosphonate analogs inhibit VanX with IC(50) of 0.48-8.21mM. These data revealed a structure-activity relationship which is that the large substituent group on β-carbon resulted in low binding affinity of the phonphonate analog to VanX. This information will be helpful to guide the design and synthesis of the tightly-binding inhibitors for VanX.
authors: Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Material Science, Northwest University, Xi'an 710069, PR China.
authors: Chao
authors: C
authors: Jia
authors: Ke-Wu
authors: KW
authors: Yang
authors: Cheng-Cheng
authors: CC
authors: Liu
authors: Lei
authors: L
authors: Feng
authors: Jian-Min
authors: JM
authors: Xiao
authors: Li-Sheng
authors: LS
authors: Zhou
authors: Yi-Lin
authors: YL
authors: Zhang
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism*; D002244:Carbon / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004151:Dipeptides / Q000737:chemistry*; D015195:Drug Design; D016983:Enterococcus / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D063065:Organophosphonates / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D010757:Phosphorous Acids / Q000737:chemistry*; D011485:Protein Binding; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase / Q000378:metabolism*; D013329:Structure-Activity Relationship; D020713:Vancomycin Resistance / Q000187:drug effects
chemical_list: D001426:Bacterial Proteins; D004151:Dipeptides; D063065:Organophosphonates; D010455:Peptides; D010757:Phosphorous Acids; C570063:phosphonic acid; D002244:Carbon; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; C091956:VanX dipeptidase