TY - JOUR
T1 - Broadening the antibacterial spectrum of histidine kinase autophosphorylation inhibitors via the use of ε-poly-L-lysine capped mesoporous silica-based nanoparticles
AU - Velikova, Nadya
AU - Mas, Nuria
AU - Miguel-Romero, Laura
AU - Polo, Lorena
AU - Stolte, Ellen
AU - Zaccaria, Edoardo
AU - Cao, Rui
AU - Taverne, Nico
AU - Murguía, José Ramón
AU - Martinez-Manez, Ramon
AU - Marina, Alberto
AU - Wells, Jerry
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Drug delivery
KW - Gram negative
KW - Multi-drug resistance
KW - Nanotechnology
KW - Two-component systems
U2 - 10.1016/j.nano.2016.09.011
DO - 10.1016/j.nano.2016.09.011
M3 - Article
AN - SCOPUS:85009860262
VL - 13
SP - 569
EP - 581
JO - Nanomedicine: Nanotechnology, Biology, and Medicine
JF - Nanomedicine: Nanotechnology, Biology, and Medicine
SN - 1549-9634
IS - 2
ER -