title: A redesigned vancomycin engineered for dual D-Ala-D-ala And D-Ala-D-Lac binding exhibits potent antimicrobial activity against vancomycin-resistant bacteria.
abstract: The emergence of bacteria resistant to vancomycin, often the antibiotic of last resort, poses a major health problem. Vancomycin-resistant bacteria sense a glycopeptide antibiotic challenge and remodel their cell wall precursor peptidoglycan terminus from d-Ala-d-Ala to d-Ala-d-Lac, reducing the binding of vancomycin to its target 1000-fold and accounting for the loss in antimicrobial activity. Here, we report [Ψ[C(═NH)NH]Tpg(4)]vancomycin aglycon designed to exhibit the dual binding to d-Ala-d-Ala and d-Ala-d-Lac needed to reinstate activity against vancomycin-resistant bacteria. Its binding to a model d-Ala-d-Ala ligand was found to be only 2-fold less than vancomycin aglycon and this affinity was maintained with a model d-Ala-d-Lac ligand, representing a 600-fold increase relative to vancomycin aglycon. Accurately reflecting these binding characteristics, it exhibits potent antimicrobial activity against vancomycin-resistant bacteria (MIC = 0.31 μg/mL, VanA VRE). Thus, a complementary single atom exchange in the vancomycin core structure (O → NH) to counter the single atom exchange in the cell wall precursors of resistant bacteria (NH → O) reinstates potent antimicrobial activity and charts a rational path forward for the development of antibiotics for the treatment of vancomycin-resistant bacterial infections.
authors.affiliation: Department of Chemistry, The Skaggs Institute for Chemical Biology, La Jolla, California 92037, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Xie
authors.forename: Joshua G
authors.initials: JG
authors.lastname: Pierce
authors.forename: Robert C
authors.initials: RC
authors.lastname: James
authors.forename: Akinori
authors.initials: A
authors.lastname: Okano
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism*; D001419:Bacteria / Q000378:metabolism; D001665:Binding Sites; D002473:Cell Wall / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism*; D010457:Peptidoglycan / Q000378:metabolism*; D014640:Vancomycin / Q000737:chemistry* / Q000378:metabolism*; D020713:Vancomycin Resistance
chemical_list: D000900:Anti-Bacterial Agents; D004151:Dipeptides; D010457:Peptidoglycan; C002956:alanylalanine; D014640:Vancomycin