Scope and limitations of targeted aggregation as means to design novel antibacterial agents

On sep 21st 2016 the UN General Assembly declared the fight against antimicrobial resistance a top-priority. An essential element in this struggle is the development of antibiotics with novel mechanisms of action in view of the increasing resistance against commonly used antibiotics. In the last twenty years almost no novel antibiotics were developed. We recently developed a novel mode of generating protein knock-down in cells by inducing aggregation of target proteins by exposure to aggregation inducing peptides (called PeptInsTM). We demonstrated proof of concept in tumor cells (Gallardo et al, Science, in press), plants (Betti et al, Plant Physiol, 2016) and showed that this mechanism can be used as a bactericidal strategy in mice infected with either Gram positive (Bednarska et al, Mol Microbiol, 2015) or Gram negative bacteria (Khodaparast et al, in preparation). Although the development of these lead molecules into actual therapeutic entities will occur in a biotech company, our findings leave a clear need to acquire more fundamental insight into the precise mechanism of targeted aggregation so that we can understand better its scope and limitations. In the current project, the Switch Laboratory and the Laboratory of Clinical Bacteriology and Mycology want to rejoin forces for this purpose. To learn about the mechanism, we will screen systematic gene knock-out libraries of the clinically relevant model organism E coli as well as genome wide cDNA libraries for genes that modify the uptake and the antibacterial effect of known antibacterial PeptIns. Moreover, we will perform time-dependent analysis of the aggregation prone fraction treated bacteria to map out the aggregation cascade that leads to bacterial death. To learn more about scope, we will screen for PeptIns that are effective against other Gram negative species for which there is an urgent clinical need (Klebsiella, Pseudomonas, Acinetobacter). Last but not least we want to explore alternative chemical structures by which to deliver the aggregation prone regions, in order to improve efficacy, stability and selectivity.

Keywords:protein kinase D

Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences