ArticleACS infectious diseases2026
Tobramycin-Peptide Nucleic Acids Synergize with Polymyxin B and Other Bioactive Compounds to Inhibit Growth of Gram-Negative Bacteria.
Article in ACS infectious diseases, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Antisense oligomers show promise for the treatment of infectious diseases but face challenges as therapeutic agents due to limited uptake in bacteria. Although cell-penetrating peptides can serve as effective delivery vehicles, they may exhibit nonspecific effects and can contribute to resistance development. Aminoglycoside-peptide nucleic acid (PNA) conjugates represent a complementary delivery strategy that leverages the intrinsic cationic and membrane-interacting properties of aminoglycosides to enhance cellular uptake. In this work, we synthesized tobramycin-PNA (TOB-PNA) conjugates targeting the translation initiation region of the acyl carrier protein gene (acpP) in Enterobacterales. Conjugation of TOB to PNA enhanced target-binding stability, improved the inhibition of translation in vitro, and enhanced activity against Gram-negative bacteria. TOB-PNA activity was further enhanced in combination with the outer membrane-permeabilizing antibiotic polymyxin B (PMB), leading to improved antibacterial activity against clinically relevant Gram-negative pathogens, including drug-resistant isolates. Resistance studies demonstrated that the TOB-PNA conjugate, both alone and in combination with PMB, maintains antibacterial activity over prolonged exposure, suggesting a higher barrier to resistance evolution than conventional TOB treatment. Mammalian toxicity studies in HEK293T cells showed IC50 > 100 μM. Morphological analyses indicated that TOB-PNA treatment induces cellular stress and division abnormalities consistent with disruption of essential metabolic pathways, while PMB increased membrane permeability. In addition, TOB-PNA behaved synergistically with other compounds targeting distinct cellular processes, including fatty acid biosynthesis (triclosan), folate metabolism (trimethoprim), and cell morphology (A22).
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