Mapping the proteostatic collapse caused by aggregation-inducing bactericidal peptides

I was part of the effort to develop a novel class of antibiotics based on the concept that short aggregation-prone regions within the protein sequence drive amyloid-like protein aggregation. I developed antimicrobial peptides called Pept-Ins that trigger an aggregation cascade in bacteria resulting in the formation of inclusion bodies, the collapse of the proteome, and the death of bacteria. Now, my goal is to better understand the antimicrobial mechanism of action of Pept-Ins to improve the design of Pept-Ins. I will compare the contents of inclusion bodies triggered by Pept-Ins and those triggered by other causes, as well as monitor the incorporation of proteins into inclusion bodies to map the aggregation cascade that results in the collapse of protein homeostasis. I will do this using an already established proteomic analysis pipeline as well as developing innovative methods to sequence the transcripts trapped in inclusion bodies and to visualise the proteostatic cascade. The importance of proteostasis for health and its decline during ageing has been recognized for a decade, but proteostasis collapse is still poorly defined. I will dissect the process of Pept-In-induced proteostatic collapse, the kinetics and consequences of Pept-Ininduced inclusion body formation to explain why Pept-In-induced inclusion bodies are lethal to bacteria, better understand the mode of action of a novel class of antibiotics as well as aid to design more potent antimicrobial Pept-Ins.