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 Eldere (), Frederic Rousseau () and Joost Schymkowitz ()
Additional contact information
Ladan Khodaparast: KULeuven
Laleh Khodaparast: KULeuven
Rodrigo Gallardo: VIB Center for Brain and Disease Research
Nikolaos N. Louros: VIB Center for Brain and Disease Research
Emiel Michiels: VIB Center for Brain and Disease Research
Reshmi Ramakrishnan: VIB Center for Brain and Disease Research
Meine Ramakers: VIB Center for Brain and Disease Research
Filip Claes: VIB Center for Brain and Disease Research
Lydia Young: University of Leeds
Mohammad Shahrooei: KULeuven
Hannah Wilkinson: VIB Center for Brain and Disease Research
Matyas Desager: VIB Center for Brain and Disease Research
Wubishet Mengistu Tadesse: KULeuven
K. Peter R. Nilsson: Linköping University
Per Hammarström: Linköping University
Abram Aertsen: KULeuven
Sebastien Carpentier: KULeuven
Johan Eldere: KULeuven
Frederic Rousseau: VIB Center for Brain and Disease Research
Joost Schymkowitz: VIB Center for Brain and Disease Research

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03131-0

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