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Project

Project type/Form of grant
Project grant
Title [sv]
Undersökning av metallo-beta-lactamase inhibitorer som målmolekyler för bekämpning av multiresistent bakteria
Title [en]
Inhibition studies of metallo-beta-lactamases as target proteins of antibiotic resistance
Abstract [sv]
The appearance of superbugs producing metallo-beta-lactamases have resulted in a clinical crisis. This project intends to express and purify subclasses of metallo-beta-lactamases including NDM-1. Specific goals are the synthesis and characterization of a series of N-heterocyclic dicarboxylic acid derivates and beta-phospholactam type transition state analogues. Their broad-spectrum inhibition activity and structure-activity relationship will be evaluated by steady-state kinetics. Special attention will be given to possible synergistic effects when applied in combination with antibiotics for inhibition of antibiotic resistant bacteria by the MIC method. Recombinant Co (II) substituted metallo-beta-lactamases will be systematically studied at the molecular level. Docking studies will be performed focusing on coordination properties and interatomic distances to elucidate the mechanism of action. The versatile association between enzyme inhibitors and the metal centres of metallo-beta-lactamases will be studied by spectroscopic (UV-Vis, NMR, EPR) and X-ray crystallographic techniques. The gained information will guide the design of new tight-binding inhibitors. The long term goal of this project is to create novel compounds with broad-spectrum inhibitory potency to MâLs and superbugs, and to provide a deeper understanding of molecular processes behind antibiotic action that is expected to support the development of additional antibacterial drugs.
Principal InvestigatorErdelyi, Mate
Coordinating organisation
Uppsala University
Funder
Period
2014-01-01 － 2018-12-31
National Category
Organic ChemistryStructural BiologyMedicinal Chemistry
Identifiers
DiVA, id: project:5052Project, id: 2013-08804_VR

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Organic ChemistryStructural BiologyMedicinal Chemistry

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