Organic Salts Based on Streptomycin: A New Approach for an Old Drug

The growing threat of bacterial resistance is expected to become a leading cause of global mortality in the coming decades. Currently, the pharmaceutical industry is focused on the discovery of new efficient antibiotics as well as the reintroduction of discontinued drugs under the hypothesis that resistance to them may have declined. Another strategy is to use enhancers or adjuvants to counteract the current resistance mechanisms. In this study, both approaches are explored by employing an out-of-market antibiotic, streptomycin, combined with biocompatible sulfonate and carboxylate anions. Eight organic salts were synthesized via direct protonation, yielding stable solids at room temperature, and characterized in terms of their physicochemical properties, such as solubility, permeability, and thermal stability. Their biological properties were also investigated, including toxicity against human keratinocytes and antimicrobial activity against both susceptible and multidrug-resistant strains of <i>Escherichia coli</i>, <i>Pseudomonas aeruginosa</i>, <i>Klebsiella pneumoniae</i>, <i>Staphylococcus aureus</i>, and <i>Staphylococcus epidermidis</i>. Among the synthesized compounds, one is an ionic liquid ([STPH₃][GluCOO]₃), while those with <i>p</i>-toluenesulfonate ([STPH₃][<i>p</i>-TolSO₃]₃), propanesulfonate ([STPH₃][C₃SO₃]₃), and glycolic acid ([STPH₃][GlyCOO]₃) showed the greatest potential for transdermal delivery due to their favorable combination of physicochemical and biological properties. [STPH₃][<i>p</i>-TolSO₃]₃ exhibited enhanced permeation in phospholipid bilayer assays along with promising biocompatibility and antimicrobial efficacy, making it a strong candidate for further investigation.