Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis

Ladan Khodaparast, Laleh Khodaparast, Rodrigo Gallardo, Nikolaos N. Louros, Emiel Michiels, Reshmi Ramakrishnan, Meine Ramakers, Filip Claes, Lydia Young, Mohammad Shahrooei, Hannah Wilkinson, Matyas Desager, Wubishet Mengistu Tadesse, K. Peter R. Nilsson, Per Hammarström, Abram Aertsen, Sebastien Carpentier, Johan Van Eldere, Frederic Rousseau, Joost Schymkowitz

Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find that most APRs are unique within a proteome, but that a small minority of APRs occur in many proteins. When aggregation is nucleated in bacteria by such frequently occurring APRs, it leads to massive and lethal inclusion body formation containing a large number of proteins. Buildup of bacterial resistance against these peptides is slow. In addition, the approach is effective against drug-resistant clinical isolates of Escherichia coli and Acinetobacter baumannii, reducing bacterial load in a murine bladder infection model. Our results indicate that redundant APRs are weak points of bacterial protein homeostasis and that targeting these may be an attractive antibacterial strategy.