Precision antisense
antibacterial agents may be developed into
novel antibiotics in the fight against multidrug-resistant Gram-negative
bacteria. In this study, a series of diaminobutanoic acid (DAB) dendrons
are presented as novel carriers for the delivery of antisense antibacterial
peptide nucleic acids (PNAs). The dendron–PNA conjugates targeting
the essential
acpP
gene exhibit specific antisense
antimicrobial bactericidal activity against
Escherichia
coli
and
Klebsiella pneumoniae
at one-digit micromolar concentrations, while showing low toxicity
to human cells. One compound selected from a structure–activity
relationship series showed high stability in mouse and human serum
(
t
1/2
≫ 24 h) as well as in vivo
activity against a multidrug-resistant, extended spectrum beta-lactamase-producing
E. coli
in a murine peritonitis model. The compound
was also well tolerated in mice upon
i.v.
administration
up to a dose of 20 mg/kg, and in vivo fluorescence imaging indicated
clearance via renal excretion with slight accumulation in the kidneys
and liver. Thus, DAB-based dendrons constitute a promising new chemistry
platform for development of effective delivery agents for antibacterial
drugs with possible in vivo use.
The size and redox properties of molecular polyoxometalates (POMs) make them extremely relevant for bioapplications: from disrupting tumour growth and enzyme inhibition, to DNA-intercalating agents and antimicrobial applications. Their unique ability to reversibly dominate and receive electrons, coupled with their high anionic charge, also makes them suitable for the preparation of zero-valent state metal nanoparticles (NPs) from molecular precursors. Polyoxometalate-stabilised nanoparticles (NPs@POM) are therefore an ideal delivery vehicle for bioactive POMs. Here we show how POM-stabilised gold NPs (AuNPs@POM) are massively internalised into Vero (kidney epithelial) and B16 (skin melanoma) cell lines with variable cytotoxic effects. Cell viability assays and quantification of cytoplasmic membrane composition revealed that the Vero cell line was unaltered by the internalisation of these hybrid particles; while their internalisation in B16 tumour cells produced mild cytotoxic effects and an antiproliferative cell cycle arrest in the G0/G1 and G2/M phases. The observed perturbation of the tumour cell line combined with the high degree of internalisation means that these (or similar) NPs@POM could serve as candidates for a range of bioapplications in diagnostics or therapy.
A series of amino-and guanidino-terminating 3-and 4-generation 2,4-diaminobutanoic acid (Dab) dendrons have been robustly synthesized on a solid phase and characterized as cellular delivery agents in antisense peptide nucleic acid (PNA) conjugates in the pLuc705 HeLa cell splice switching system. The dendron−PNA conjugates exhibited splice correction activity at one digit micromolar concentrations, and guanidino-terminating dendrons were significantly more effective than analogous amine terminating ones. Furthermore, introduction of lipophilic groups such as phenyl, alkyl, or fatty acids increased efficacy, but also increased cellular toxicity. Fluorescence microscopy analyses supported an endosomal uptake mechanism and furthermore predominantly showed colocalization with late endosomes and lysosomes. The robust solid phase synthesis should make such Dab−dendrons a useful platform for further in vitro as well as in vivo optimization.
DFT calculations and experimental data prove that the [Na{(MoV2O4)3(μ2-O)3(μ2-SO3)3(μ6-SO3)}2]15− POM is capable of completely reducing Au(iii) to Au(0).
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