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Title [sv]
Combinatorials: Nya medel och kombinationer mot bakteriell tillväxt, överlevnad och uthållighet; från high-throughput screening till verkningsmekanismer
Title [en]
Combinatorials: Novel drugs and drug combinations against bacterial growth, survival and persistence; from high-­? throughput screening to mechanism of action
Abstract [en]
Control of bacterial infections is threatened by the rapid emergence of drug resistance, drug tolerance that mitigates antimicrobial efficacy, and the lack of new antibiotics in recent years. Combination treatments and/or re-purposing of known drugs can provide a cost- and time-efficient solution. We propose a comprehensive and powerful strategy to repurpose or improve FDA-approved drugs including neglected/disused (ND) antibiotics, and identify combinations to re-sensitize resistant/tolerant bacteria. Using high-throughput screening (HTS), we will test thousands of pairwise drug combinations on bacterial growth, viability and bacterial persistence in three clinically relevant pathogens: uropathogenic Escherichia coli (UPEC), Staphylococcus aureus (Sa), and Streptococcus pneumoniae (Sp). Our scope thus spans the Gram-negative/-positive divide, and targets several bacterial states implicated in both acute and chronic infections, including pneumonia, pyelonephritis, bacteremia and endocarditis. To optimize antimicrobial treatment, we will use state-of-the-art and further advance translational pharmacokinetic (PK)/ pharmacodynamic (PD) modeling. This will prioritize and validate lead combinations, which will be tested in resistant clinical isolates, for toxicity in cell-based assays and for efficacy in several animal models. In vivo PK/PD modeling will also be performed for our top leading combinations.
Principal InvestigatorUhlin, Bernt Eric
Coordinating organisation
Umeå University
Funder
Period
2015-12-01 － 2018-11-30
National Category
Other Medical Biotechnology
Identifiers
DiVA, id: project:1502Project, id: 2015-06824_VR

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