Cardiolipin-Based Lipopolyplex Platform for the Delivery of Diverse Nucleic Acids into Gram-Negative Bacteria

Abstract

Antibiotic resistance is a growing public health concern. Because only a few novel classes of antibiotics have been developed in the last 40 years, such as the class of oxazolidinones, new antibacterial strategies are urgently needed (Coates, A.R. et al., 2011). Nucleic acid-based antibiotics are a new type of antimicrobials. However, free nucleic acids cannot spontaneously cross the bacterial cell wall and membrane; consequently, their intracellular delivery into bacteria needs to be assisted. Here, we introduce an original lipopolyplex system named liposome polymer nucleic acid (LPN), capable of versatile nucleic acid delivery into bacteria. We characterized LPN formed with significant therapeutic nucleic acids: 11 nt antisense single-stranded (ss) DNA and double-stranded (ds) DNA of 15 and 95 base pairs (bp), 9 kbp plasmid DNA (pDNA), and 1000 nt ssRNA. All these complexes were efficiently internalized by two different bacterial species, i.e., Escherichia coli and Pseudomonas aeruginosa, as shown by flow cytometry. Consistent with intracellular delivery, LPN prepared with an antisense oligonucleotide and directed against an essential gene, induced specific and important bacterial growth inhibition likely leading to a bactericidal effect. Our findings indicate that LPN is a versatile platform for efficient delivery of diverse nucleic acids into Gram-negative bacteria.

Erythromycin loaded by tetrahedral framework nucleic acids are more antimicrobial sensitive against Escherichia coli (E. coli)

“…With the rapid development of DNA nanotechnology, a variety of self-assembled DNA nanomaterial with different sizes and spatial structures have been developed. The list of applications of DNA nanostructure research is endless in the field of molecular biology, including the use of these nanomaterials as -biosensors, vehicles, for drug delivery, and so on [ [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] ]. At present, the antibacterial application of DNA nanostructures mainly focused on optimizing bactericidal performance and cytotoxicity by combining these nanostructures with other antibacterial substances [ [38] , [39] , [40] , [41] ].…”

Tetrahedral Framework Nucleic Acids Loading Ampicillin Improve the Drug Susceptibility against Methicillin-Resistant Staphylococcus aureus

“…Third, Ji-Hyun Yeom et al utilized NAM with an antimicrobial peptide to improve the penetrative ability of the antimicrobial peptide . Fourthly, the combination of NAM and metal nanoparticles can reduce the cytotoxicity of metal nanoparticles and maintain its killing effect. , Finally, NAM combined with traditional antibiotics enhances antibiotic efficacy and reduces the requirement for high doses of antibiotics. − Nanomedicines have been widely studied and used as antibacterial choice. , DNA nanostructures, used alone or functionalized with specific DNA sequences, are used as an antimicrobial therapy for severe bacterial infection. ,− Tetrahedral framework nucleic acids (tFNAs) are self-assembled by four single-stranded DNA (ssDNA) molecules via highly specific base pairing. − Our previous studies showed that tFNAs have excellent biocompatibility and inherent nontoxicity to bacterial and mammalian cells. − The size and structure of tFNAs can be accurately regulated; thus, it is a suitable therapeutic delivery vehicle to deliver antitumor drugs to tumor cells and restore the sensitivity of chemotherapy drugs . Moreover, tFNAs could transfer antisense peptide nucleic acids to drug-resistant bacteria and enhance its bactericidal effect …”

Promising strategies employing nucleic acids as antimicrobial drugs

“…Several essential genes such as the gyrA , ftsZ , and acpP have already been recognized as potential targets for antimicrobial ASOs. 11 , 16 , 18 , 24 , 29 , 30 , 31 , 32 , 33 , 34 , 35 Despite being prevalent in a wide range of both Gram-negative and Gram-positive pathogens, 11 , 16 , 17 , 18 , 24 , 26 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 the presence of mutations in these genes can pose challenges in designing broad-spectrum ASOs. However, they still serve as suitable targets for narrow-spectrum ASOs.…”

“… E. coli ; P. aeruginosa Perche et al. 42 EPC/DMPG/PEG2000-DSPE liposomes (molar ratio: 14:0.9:1) loaded with PS/DNA-PEI complexes (N/P ratio: 8) MIC: 3 μg/mL (0.5 μM) Resistance gene inhibition: 100 μg/mL (17.4 μM) N.A. MDR– P. aeruginosa Wang et al.…”