The disulfide bond as a chemical tool in cyclic peptide antibiotics: engineering disulfide polymyxins and murepavadin

RISE´s main contribution to the project concerns assessments and tests of the toxicity and tolerability of the test substances in accordance with praxis for drug development.

RISE toxicological expertise will be advisory throughout the project time and ensures that safety studies in vivo will not start until there is a scientific basis for these studies.

The mouse will be the animal model studied primarily because it is the most relevant rodent based on known scientific information.Once the project has reached candidate drug (CD) prenomination, general toxicological studies start in vivo.

Maximum tolerable dose (MTD) and Dose-range-finding (DRF) in rodents is the first to be studied and aims to define the highest tolerated dose, ie a treatment that does not cause unacceptable adverse effects or toxicity.

In an MTD/DRF study (1- and 7-days study phases), the adverse effects of the drug candidate are investigated by:Observations of clinical signsHematology - detailed blood analysis, with an assessment of the most important leukocyte populationsClinical chemistry - wide range of biochemical parameters for bloodSpecific measurements of adaptive parameters for renal toxicityHistopathological changesBioanalysis of test compound, including plasma concentration determinationn.Toxicokinetic analysis and profileThe results will give relevant guidance for further decisions in the project, e.g.

CD selection and dose level selection in subsequent regulatory general toxicology studies.