title: Cell permeable vanX inhibitors as vancomycin re-sensitizing agents.
abstract: VanX is an induced zinc metallo d-Ala-d-Ala dipeptidase involved in the viable remodeling of bacterial cell wall that is essential for the development of VREF. Here we report two cyclic thiohydroxamic acid-based peptide analogs that were designed, synthesized and investigated as vancomycin re-sensitizing agents. These compounds exhibit low micromolar inhibitory activity against vanX, with low cytotoxicity and were shown to increase vancomycin sensitivity against VREF. The improved pharmacological properties of these novel inhibitors over previous transition state mimics should provide an enhanced platform for designing potent vanX inhibitors for overcoming vancomycin resistance.
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, 717 Delaware St SE, Minneapolis, MN 55455, United States; Department of Experimental & Clinical Pharmacology, University of Minnesota, 717 Delaware St SE, Minneapolis, MN 55455, United States. Electronic address: muthy003@umn.edu.
authors.forename: Ramaiah
authors.initials: R
authors.lastname: Muthyala
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, 717 Delaware St SE, Minneapolis, MN 55455, United States; Department of Experimental & Clinical Pharmacology, University of Minnesota, 717 Delaware St SE, Minneapolis, MN 55455, United States.
authors.forename: Namrata
authors.initials: N
authors.lastname: Rastogi
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, United States.
authors.forename: Woo Shik
authors.initials: WS
authors.lastname: Shin
authors.affiliation: Department of Experimental & Clinical Pharmacology, University of Minnesota, 717 Delaware St SE, Minneapolis, MN 55455, United States.
authors.forename: Marnie L
authors.initials: ML
authors.lastname: Peterson
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, United States. Electronic address: shamx002@umn.edu.
authors.forename: Yuk Yin
authors.initials: YY
authors.lastname: Sham
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D015394:Molecular Structure; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D014640:Vancomycin; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; C091956:VanX dipeptidase
keywords: Antibiotics; Drug resistance; Pyrithione; Thiohydroxamic acid; VanX; Vancomycin