Modified horseshoe crab peptides target and kill bacteria inside host cells
0301 basic medicine
570
571
Erythrocytes
[SDV.IMM] Life Sciences [q-bio]/Immunology
Primary Cell Culture
610
Bone Marrow Cells
Peptides, Cyclic
Mice
03 medical and health sciences
Horseshoe Crabs
Uropathogenic Escherichia coli
Animals
Humans
Cells, Cultured
Intracellular niche
Bacteria
Macrophages
Cell Membrane
Bacterial Infections
Host defence
Anti-Bacterial Agents
DNA-Binding Proteins
Mice, Inbred C57BL
Selective membrane-active mechanism
[SDV.IMM]Life Sciences [q-bio]/Immunology
Antimicrobial peptide
Antimicrobial Peptides
Antimicrobial Cationic Peptides
DOI:
10.1007/s00018-021-04041-z
Publication Date:
2021-12-31T05:02:24Z
AUTHORS (13)
ABSTRACT
Bacteria that occupy an intracellular niche can evade extracellular host immune responses and antimicrobial molecules. In addition to classic intracellular pathogens, other bacteria including uropathogenic Escherichia coli (UPEC) can adopt both extracellular and intracellular lifestyles. UPEC intracellular survival and replication complicates treatment, as many therapeutic molecules do not effectively reach all components of the infection cycle. In this study, we explored cell-penetrating antimicrobial peptides from distinct structural classes as alternative molecules for targeting bacteria. We identified two β-hairpin peptides from the horseshoe crab, tachyplesin I and polyphemusin I, with broad antimicrobial activity toward a panel of pathogenic and non-pathogenic bacteria in planktonic form. Peptide analogs [I11A]tachyplesin I and [I11S]tachyplesin I maintained activity toward bacteria, but were less toxic to mammalian cells than native tachyplesin I. This important increase in therapeutic window allowed treatment with higher concentrations of [I11A]tachyplesin I and [I11S]tachyplesin I, to significantly reduce intramacrophage survival of UPEC in an in vitro infection model. Mechanistic studies using bacterial cells, model membranes and cell membrane extracts, suggest that tachyplesin I and polyphemusin I peptides kill UPEC by selectively binding and disrupting bacterial cell membranes. Moreover, treatment of UPEC with sublethal peptide concentrations increased zinc toxicity and enhanced innate macrophage antimicrobial pathways. In summary, our combined data show that cell-penetrating peptides are attractive alternatives to traditional small molecule antibiotics for treating UPEC infection, and that optimization of native peptide sequences can deliver effective antimicrobials for targeting bacteria in extracellular and intracellular environments.
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CITATIONS (14)
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