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

Bálint KintsesPramod K JangirGergely FeketeMónika SzámelOrsolya MéhiRéka SpohnLejla DarukaAna MartinsAli HosseinniaAlla GagarinovaSunyoung KimSadhna PhanseBálint CsörgőÁdám GyörkeiEszter AriViktória LázárIstván NagyMohan BabuCsaba PálBalazs Papp
Published in: Nature communications (2019)
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.
Keyphrases
  • escherichia coli
  • endothelial cells
  • genome wide
  • dna methylation
  • drug delivery
  • single cell
  • pluripotent stem cells
  • amino acid
  • klebsiella pneumoniae