Chemical-genetic profiling reveals limited cross-resistance between antimicrobial peptides with different modes of action

Bálint Kintses, Pramod K. Jangir, Gergely Fekete, Mónika Számel, Orsolya Méhi, Réka Spohn, Lejla Daruka, Ana Martins, Ali Hosseinnia, Alla Gagarinova, Sunyoung Kim, Sadhna Phanse, Bálint Csörgő, Ádám Györkei, Eszter Ari, Viktória Lázár, István Nagy, Mohan Babu, Csaba Pál, Balázs Papp

Research output: Contribution to journalArticle

Abstract

Antimicrobial peptides (AMPs) are key effectors of the innate immune system and promising therapeutic agents. Yet, knowledge on how to design AMPs with minimal cross-resistance to human host-defense peptides remains limited. Here, we systematically assess the resistance determinants of Escherichia coli against 15 different AMPs using chemical-genetics and compare to the cross-resistance spectra of laboratory-evolved AMP-resistant strains. Although generalizations about AMP resistance are common in the literature, we find that AMPs with different physicochemical properties and cellular targets vary considerably in their resistance determinants. As a consequence, cross-resistance is prevalent only between AMPs with similar modes of action. Finally, our screen reveals several genes that shape susceptibility to membrane- and intracellular-targeting AMPs in an antagonistic manner. We anticipate that chemical-genetic approaches could inform future efforts to minimize cross-resistance between therapeutic and human host AMPs.

Original languageEnglish
Article number5731
JournalNature communications
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Kintses, B., Jangir, P. K., Fekete, G., Számel, M., Méhi, O., Spohn, R., Daruka, L., Martins, A., Hosseinnia, A., Gagarinova, A., Kim, S., Phanse, S., Csörgő, B., Györkei, Á., Ari, E., Lázár, V., Nagy, I., Babu, M., Pál, C., & Papp, B. (2019). Chemical-genetic profiling reveals limited cross-resistance between antimicrobial peptides with different modes of action. Nature communications, 10(1), [5731]. https://doi.org/10.1038/s41467-019-13618-z