L. Khodaparast, L. Khodaparast, R. Gallardo, N. N. Louros, E. Michiels, R. Ramakrishnan, M. Ramakers, F. Claes, L. Young, M. Shahrooei, H. Wilkinson, M. Desager, W. M. Tadesse, K. P. R. Nilsson, P. Hammarström, A. Aertsen, S. Carpentier, J. Van Eldere, F. Rousseau and J. Schymkowitz
Nature Communications 9, 866 (2018)
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 Aci- netobacter 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.