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.

Analyses in zebrafish embryos reveal that nanotoxicity profiles are dependent on surface-functionalization controlled penetrance of biological membranes

“…To date, the zebrafish has mainly been used as an in vivo model to evaluate the toxicity of selected therapeutic MSNs, with a specific emphasis on the effect of the particles on adult or embryonic mortality 20 , 21 . A few studies have used the model to assess in vivo delivery potential 22 , or therapeutic efficacy.…”

Targeted Stimuli-Responsive Mesoporous Silica Nanoparticles for Bacterial Infection Treatment

“…It is also possible to go a step beyond, by using cationic polymers not only as targeting ligands that increase antimicrobial effect of loaded cargo, but also as responsive pore gatekeepers that hinder premature drug release until exposure to target stimulus. In this line, Martínez-Máñez and co-workers reported the enhancement of the efficacy and broadening the spectrum of antibacterial agents, namely vancomycin (VAN) and histidine kinase autophosphorylation inhibitors (HKAIs), [ 48 , 49 ] by developing ε-poly-L-lysine (ε-pLys)-capped MSNs as bacteria-responsive nanocarriers, as will be discussed in detail in Section 3.1.3 . The results indicated that the enhancement of antimicrobials toxicity to Gram-negative bacteria is due to the bacterial wall damage induced by positively-charged ε-pLys, which allows the entrapped cargo to gain access into the cell (vide infra).…”

Mesoporous Silica‐Based Materials with Bactericidal Properties

“…Using a similar approach, Velikova et al prepared different gated MS NPs loaded with histidine kinase autophosphorylation inhibitors (HKAIs). Pores of the loaded support were again functionalized with N ‐[(3‐trimethoxysilyl) propyl]ethylendiamine triacetic acid trisodium salt and capped with ε‐PL . Antimicrobial tests using the prepared nanoparticles against E. coli and Serratia marcescens showed higher activity than free HKAIs.…”