Masterarbeit

Pathway to non-clinical development of Colicin U as an alternative antibiotic

Dr. Holger Cynis (2025)

Summary 

Due to emerging occurrence of resistance mechanisms of bacteria against classical antibiotics, an urgent need for the development of alternative antibiotics exists. Strategies to identify such compounds comprise the re-consideration of understudied or early de-prioritized natural molecules. 

In this regard, Colicin U (ColU) belongs to a larger group of proteinaceous substances (Bacteriocins) that target closely related bacterial species in the course of an intra-species competition. ColU was first described in 1987 and gained attention due to its ability to kill multi-drug resistant isolates of E. coli. The present master thesis experimental steps towards the non-clinical development of ColU as alternative antibiotic were presented and discussed.

For the non-clinical development of ColU, specific antibodies were developed, which were combined in an ELISA method, that is able to detect ColU in different matrices from different species. The assay method was validated under GLP in order to be used in pivotal toxicological studies. Using this assay pharmacokinetic parameters could be determined, enabling efficacy studies of ColU in a model of E. coli-related septicemia in mice.

Safety studies using isolated proteins and cell cultures were performed in order to identify ColU concentrations that do not interfere with cellular function. Afterwards toxicological studies in rodent and non-rodent species were conducted (rodent) and or were initiated at the time of submission of the thesis (non-rodent). Overall, the non-clinical studies showed the therapeutic potential of ColU but also revealed points to consider to prevent side effects in clinical studies.

Pages: 79