Abstract
Bacterial resistance to antibiotics threatens the ability to treat life-threatening bloodstream infections. Oligonucleotides (ONs) composed of nucleic acid mimics (NAMs) able to inhibit essential genes can become an alternative to traditional antibiotics, as long as they are safely transported in human serum upon intravenous administration and they are carried across the multilayered bacterial envelopes, impermeable to ONs. In this study, fusogenic liposomes were considered to transport the ONs and promote their internalization in clinically relevant bacteria. Locked nucleic acids and 2′-OMethyl RNA were evaluated as model NAMs and formulated into DOTAP–DOPE liposomes followed by post-PEGylation. Our data showed a complexation stability between the post-PEGylated liposomes and the ONs of over 82%, during 24 h in native human serum, as determined by fluorescence correlation spectroscopy. Quantification by a lipid-mixing assay showed that liposomes, with and without post-PEGylation, fused with all bacteria tested. Such fusion promoted the delivery of a fraction of the ONs into the bacterial cytosol, as observed by fluorescence in situ hybridization and bacterial fractionation. In short, we demonstrated for the first time that liposomes can safely transport ONs in human serum and intracellularly deliver them in both Gram-negative and -positive bacteria, which holds promise towards the treatment of bloodstream infections.
Highlights
Antimicrobial resistance (AMR) is an increasing major public health concern, and the scientific community is struggling to find alternatives as we are entering the post-antibiotic era [1]
Oligonucleotides (ONs) composed of nucleic acid mimics (NAMs) such as locked nucleic acids (LNAs), able to resist the degradation by nucleases and with impressive binding affinity for complementary RNA, have the potential to modulate the expression of specific genes and hold promise as alternative drugs to conventional antibiotics [5,6,7]
Upon PEGylation of the lipoplexes, the final zeta potential of the lipoplexes decreased to +14 ± 3 mV and the average hydrodynamic diameter increased to 112 ± 10 nm, while the PDI did not vary significantly
Summary
Antimicrobial resistance (AMR) is an increasing major public health concern, and the scientific community is struggling to find alternatives as we are entering the post-antibiotic era [1]. Oligonucleotides (ONs) composed of nucleic acid mimics (NAMs) such as locked nucleic acids (LNAs), able to resist the degradation by nucleases and with impressive binding affinity for complementary RNA, have the potential to modulate the expression of specific genes and hold promise as alternative drugs to conventional antibiotics [5,6,7]. They are designed to inhibit the expression of an essential bacterial gene, leading to bacterial cell death, or inhibit a gene associated with antibiotic resistance, turning
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