title: Engineering persister-specific antibiotics with synergistic antimicrobial functions.
abstract: Most antibiotics target growth processes and are ineffective against persister bacterial cells, which tolerate antibiotics due to their reduced metabolic activity. These persisters act as a genetic reservoir for resistant mutants and constitute a root cause of antibiotic resistance, a worldwide problem in human health. We re-engineer antibiotics specifically for persisters using tobramycin, an aminoglycoside antibiotic that targets bacterial ribosomes but is ineffective against persisters with low metabolic and cellular transport activity. By giving tobramycin the ability to induce nanoscopic negative Gaussian membrane curvature via addition of 12 amino acids, we transform tobramycin itself into a transporter sequence. The resulting molecule spontaneously permeates membranes, retains the high antibiotic activity of aminoglycosides, kills E. coli and S. aureus persisters 4-6 logs better than tobramycin, but remains noncytotoxic to eukaryotes. These results suggest a promising paradigm to renovate traditional antibiotics.
authors.affiliation: Bioengineering Department, Chemistry and Biochemistry Department, and California NanoSystems Institute, University of California, Los Angeles , 410 Westwood Plaza, Los Angeles, California 90095-1600, United States.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Schmidt
authors.forename: Stephanie
authors.initials: S
authors.lastname: Deshayes
authors.forename: Sinead
authors.initials: S
authors.lastname: Hawker
authors.forename: Alyssa
authors.initials: A
authors.lastname: Blacker
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Kasko
authors.forename: Gerard C L
authors.initials: GC
authors.lastname: Wong
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects; D051379:Mice; D041681:NIH 3T3 Cells; D013211:Staphylococcus aureus / Q000166:cytology / Q000187:drug effects; D014031:Tobramycin / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D014031:Tobramycin
keywords: aminoglycoside; antibiotics; bacterial resistance; cell-penetrating peptide; drug design