Lipid oligonucleotides as a new strategy for tackling the antibiotic resistance

Abstract

Antibiotic resistance has become a major issue in public health especially for one of the most used antibiotics; the third-generation cephalosporins. one of the main resistance mechanisms in Enterobacteriaceae, is the production of extended-Spectrum β-lactamases. Here, we demonstrated that the oligonucleotide therapy is an efficient approach to reduce the resistance of bacteria to antibiotic treatment. Lipid oligonucleotides (LONs) were proved to be efficient strategies in both delivering the oligonucleotide sequences in the prokaryotic cells and decreasing the Minimum inhibitory concentration of resistant bacteria to a third generation cephalosporin, the ceftriaxone. Accordingly, we demonstrated the strong antimicrobial potential of this Lon strategy targeting the ß-lactamase activity on both clinical and laboratory strains. our results support the concept that the self-delivery of oligonucleotide sequences via lipid conjugation may be extended to other antimicrobial drugs, which opens novel ways to struggle against the antibiotic resistance.

Amphiphilic “Like-A-Brush” Oligonucleotide Conjugates with Three Dodecyl Chains: Self-Assembly Features of Novel Scaffold Compounds for Nucleic Acids Delivery

“…Due to their amphipathic nature, oligonucleotide conjugates with lipophilic groups can self-assemble in aqueous solutions and form micelles [ 10 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ] and their aggregates [ 10 , 11 , 14 ], vesicular assemblies [ 19 , 20 ], and more complex self-aggregation structures [ 2 , 11 , 21 ]. Generally, these structures are nearly spherical in shape [ 10 , 15 , 16 , 20 , 22 , 23 ].…”

Nucleic Acid Hybrids as Advanced Antibacterial Nanocarriers

“…Nevertheless, binding studies were conducted within 15 minutes, whereas uptake was seen within 3 h. Spurred on by these advancements, we have the opportunity to improve bacteria detection to address the slow, imprecise and erroneous conventional approach currently used in detecting infections. In restoring bacteria sensitivity to antibiotics, ESBLs were targeted by the two reviewed studies, given their popularity as the main resistance mechanisms in enterobacteria [129,134]. While both approaches saw increased sensitivity to cephalosporins, greater potency is seen for the lipid-modified conjugates and their micellar nanostructures (~26×) compared to the tetrahedral system (~2×).…”

“…At the optimal ratio, the efficacy of the hybrid system was enhanced from ~85% to ~99% against E. coli and from ~1% to ~32% against P. gingivalis. To demonstrate that other modifications of the nucleic acids can achieve a similar effect, Kauss and colleagues reported the fabrication of oligonucleotide hybrid nanostructures featuring a lipid oligonucleotide with complementary sequences to CTX-M extended spectrum -β-lactamases (ESBLs) as an efficient approach to reduce the resistance of pathogenic bacteria to antibiotic treatment [134]. The oligonucleotide conjugates self-assembled in aqueous solutions to form micelles (10 nm) with a hydrophobic lipid core and an oligonucleotide corona ( Figure 5A).…”

“…(A) Schematic representation of the chemical structures of lipid antisense conjugates and its subsequent self-assembly to a micelle. Reproduced with permission from[134]. Copyright Springer Nature, 2020.…”

“…(B) In vitro effect of the hybrid on the MIC of ceftriaxone and on bacteria viability of a resistant laboratory (TcK12) and clinical strain (Ec3536). Reproduced with permission from[134]. Copyright Springer Nature, 2020.…”