Abstract Antimicrobial resistance is a current public health challenge. In line with new One Health policy and World Health Organization priority pathogen list, this study explores antisense oligonucleotides targeting ß-lactamase CTX-M-15, responsible for one of the most prevalent mechanisms of resistance to third-generation cephalosporins in enterobacteria. Alternatively to common PNA chemistry, 22 different combinations of chemical modifications were designed to address main hurdles of intra-bacterial oligonucleotide efficient delivery and stability. Chemical modifications included nucleolipid conjugation and backbone chemical modifications (PTO, 2′OMe, 2′MOE, and LNA). Self-assembly properties, biophysical and thermodynamic characterization were further considered along with cell-free translation assays of ß-lactamase. The therapeutic potential was screened through minimal inhibitory concentration (MIC) to ceftriaxone. Our results demonstrated reproducible micellar self-assembly for all nucleolipid conjugates. Whereas nucleolipid conjugation in terms of thermodynamics can decrease the binding affinity for some chemistries, further inducing still efficient but lower ß-lactamase inhibition, it remained essential for in cellulo effects of decreasing antibiotic resistance. While most chemical modifications turned out to be efficient, the most potent chemistry was MOE PTO gapmer, providing the lowest binding affinity and highest ß-lactamase inhibition. This work demonstrated the interest of nucleolipid conjugation along with backbone modifications to address the challenge of antimicrobial resistance.
Barry et al. (Thu,) studied this question.
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