Ladan Khodaparast
University of Leuven, Belgium
Title: Multi-targeted proteostatic collapse as an antimicrobial strategy against multiresistant Escherichia coli
Biography
Biography: Ladan Khodaparast
Abstract
This is a novel designer antibiotics paradigm that exploits protein aggregation to kill pathogenic E. coli by widespread proteostatic collapse. In order to induce multi-targeted protein aggregation, we designed P2, a synthetic peptide containing a short aggregation-nucleating sequence that is highly redundant in the E. coli proteome. P2 is readily internalized by E. coli, inducing rapid formation of large polar inclusions resulting from co-aggregation between P2 with bacterial proteins containing similar aggregation prone sequences, resulting in a lethal aggregation cascade involving over 300 proteins connected through a network of associated APRs. P2 is active against clinical isolates that are resistant to multiple antibiotics and is effective in reducing bacterial load in bladder infection in mouse. Our results indicate slow development of resistance, suggesting that aggregation of redundant APRs constitutes a tight proteostatic deadlock. Exploiting this finding could be useful as a novel therapeutic approach against drug-resistant bacteria.