Broadening the antibacterial spectrum of histidine kinase autophosphorylation inhibitors via the use of ε-poly-L-lysine capped mesoporous silica-based nanoparticles

Nadya Velikova*, Nuria Mas, Laura Miguel-Romero, Lorena Polo, Ellen Stolte, Edoardo Zaccaria, Rui Cao, Nico Taverne, José Ramón Murguía, Ramon Martinez-Manez, Alberto Marina, Jerry Wells

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)

Abstract

Two-component systems (TCS) regulate diverse processes such as virulence, stress responses, metabolism and antibiotic resistance in bacteria but are absent in humans, making them promising targets for novel antibacterials. By incorporating recently described TCS histidine kinase autophosphorylation inhibitors (HKAIs) into ε-poly-L-lysine capped nanoparticles (NPs) we could overcome the Gram negative (Gr−) permeability barrier for the HKAIs. The observed bactericidal activity against Gr− bacteria was shown to be due to the enhanced delivery and internalization of the HKAIs and not an inhibitory or synergistic effect of the NPs. The NPs had no adverse effects on mammalian cell viability or the immune function of macrophages in vitro and showed no signs of toxicity to zebrafish larvae in vivo. These results show that HKAIs are promising antibacterials for both Gr− and Gr + pathogens and that NPs are a safe drug delivery technology that can enhance the selectivity and efficacy of HKAIs against bacteria.
Original languageEnglish
Pages (from-to)569-581
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume13
Issue number2
DOIs
Publication statusPublished - 2017

Keywords

  • Drug delivery
  • Gram negative
  • Multi-drug resistance
  • Nanotechnology
  • Two-component systems

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