Exploring Antibiotic-Potentiating Effects of Tobramycin-Deferiprone Conjugates in Pseudomonas aeruginosa

Metal ions, including Fe3+, affect the target site binding of some antibiotics and control the porin- and siderophore-mediated uptake of antibiotics. Amphiphilic tobramycins are an emerging class of antibiotic potentiators capable of synergizing with multiple classes of antibiotics against Gram-negative bacteria, including Pseudomonas aeruginosa. To study how the antibiotic-potentiating effect of amphiphilic tobramycins is affected by the presence of intermolecular iron chelators, we conjugated the FDA-approved iron chelator deferiprone (DEF) to tobramycin (TOB). Three TOB-DEF conjugates differing in the length of the carbon tether were prepared and tested for antibacterial activity and synergistic relationships with a panel of antibiotics against clinical isolates of P. aeruginosa. While all TOB-DEF conjugates were inactive against P. aeruginosa, the TOB-DEF conjugates strongly synergized with outer-membrane-impermeable antibiotics, such as novobiocin and rifampicin. Among the three TOB-DEF conjugates, 1c containing a C-12 tether showed a remarkable and selective potentiating effect to improve the susceptibility of multidrug-resistant P. aeruginosa isolates to tetracyclines when compared with other antibiotics. However, the antibacterial activity and antibiotic-potentiating effect of the optimized conjugate was not enhanced under iron-depleted conditions, indicating that the function of the antibiotic potentiator is not affected by the Fe3+ concentration.

Automated summary

Metal ions, including Fe3+, influence the binding of antibiotics and the uptake of antibiotics by bacteria. Amphiphilic tobramycins, a new class of antibiotic potentiators, synergize with various antibiotics against Gram-negative bacteria. In this study, iron-deferoxamine conjugates were prepared and tested for their antibacterial activity and synergistic effects with antibiotics. The conjugates showed strong synergistic effects with outer-membrane-impermeable antibiotics and selectively improved the susceptibility of multidrug-resistant bacteria to tetracyclines. However, the antibiotic potentiating effect was not influenced by the Fe3+ concentration.