title: Broadening the antibacterial spectrum of histidine kinase autophosphorylation inhibitors via the use of ε-poly-L-lysine capped mesoporous silica-based nanoparticles.
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.
authors.affiliation: Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas (CSIC), Jaume Roig 11, Valencia, Spain; Host-Microbe Interactomics Chair Group, Animal Sciences, University of Wageningen, P.O. Box 338, The Netherlands. Electronic address: nadya.velikova@wur.nl.
authors.forename: Nadya
authors.initials: N
authors.lastname: Velikova
authors.affiliation: Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Unidad Mixta Universitat Politècnica de València-Universitat de València, Departamento de Quimica, Univesidad Politecnica de Valencia, Camino de Vera s/n, 46022, Valencia, Spain; CIBER de Bioingeneria, Biomateriales y Nanomedicina, (CIBERBBN).
authors.forename: Nuria
authors.initials: N
authors.lastname: Mas
authors.affiliation: Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas (CSIC), Jaume Roig 11, Valencia, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Miguel-Romero
authors.affiliation: Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Unidad Mixta Universitat Politècnica de València-Universitat de València, Departamento de Quimica, Univesidad Politecnica de Valencia, Camino de Vera s/n, 46022, Valencia, Spain; CIBER de Bioingeneria, Biomateriales y Nanomedicina, (CIBERBBN).
authors.forename: Lorena
authors.initials: L
authors.lastname: Polo
authors.affiliation: Host-Microbe Interactomics Chair Group, Animal Sciences, University of Wageningen, P.O. Box 338, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Stolte
authors.affiliation: Host-Microbe Interactomics Chair Group, Animal Sciences, University of Wageningen, P.O. Box 338, The Netherlands.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Zaccaria
authors.affiliation: Host-Microbe Interactomics Chair Group, Animal Sciences, University of Wageningen, P.O. Box 338, The Netherlands.
authors.forename: Rui
authors.initials: R
authors.lastname: Cao
authors.affiliation: Host-Microbe Interactomics Chair Group, Animal Sciences, University of Wageningen, P.O. Box 338, The Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: Taverne
authors.affiliation: Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Unidad Mixta Universitat Politècnica de València-Universitat de València, Departamento de Quimica, Univesidad Politecnica de Valencia, Camino de Vera s/n, 46022, Valencia, Spain; CIBER de Bioingeneria, Biomateriales y Nanomedicina, (CIBERBBN).
authors.forename: José Ramón
authors.initials: JR
authors.lastname: Murguía
authors.affiliation: Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Unidad Mixta Universitat Politècnica de València-Universitat de València, Departamento de Quimica, Univesidad Politecnica de Valencia, Camino de Vera s/n, 46022, Valencia, Spain; CIBER de Bioingeneria, Biomateriales y Nanomedicina, (CIBERBBN).
authors.forename: Ramon
authors.initials: R
authors.lastname: Martinez-Manez
authors.affiliation: Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas (CSIC), Jaume Roig 11, Valencia, Spain; CIBER de Enfermedades Raras (CIBERER), ISCIII, Valencia, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Marina
authors.affiliation: Host-Microbe Interactomics Chair Group, Animal Sciences, University of Wageningen, P.O. Box 338, The Netherlands.
authors.forename: Jerry
authors.initials: J
authors.lastname: Wells
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016503:Drug Delivery Systems; D006090:Gram-Negative Bacteria; D006094:Gram-Positive Bacteria; D006639:Histidine; D000071677:Histidine Kinase; D006801:Humans; D008239:Lysine; D053758:Nanoparticles; D012822:Silicon Dioxide
chemical_list: D000900:Anti-Bacterial Agents; D006639:Histidine; D012822:Silicon Dioxide; D000071677:Histidine Kinase; D008239:Lysine
keywords: Drug delivery; Gram negative; Multi-drug resistance; Nanotechnology; Two-component systems