Tetracyclines and -lactam antibiotics are affected by multiple bacterial resistance mechanisms. One of the major resistance pathways is the alteration of the outer membrane and porin channels that prevent the entry of antibiotics into the periplasmic space. To address this issue, iron-chelators have been attached to -lactam antibiotics to facilitate entry through a siderophore-mediated uptake system and by-pass porin channels such as cefiderocol. Alternatively, potent membrane permeabilizing agents are being developed that can disrupt the outer membrane to increase antibiotics influx, such as tobramycin-based hybrids. Several reports also suggests that the nonselective metal ion binding of tetracycline affects interactions with the target-site. Iron-chelator like deferiprone has been shown to be useful in addressing this non-selectivity by facilitating the binding of tetracycline to the target. Therefore, we hypothesize that we can utilize both properties in a hybrid molecule, i.e., membrane permeabilization and iron-chelation, to overcome tetracycline resistance against Gram-negative bacteria.

This M.Sc. thesis focuses on the development of novel hybrids of tobramycin-deferiprone. Total six hybrids and two control compounds were synthesized and tested against Gram-negative bacteria, especially; Pseudomonas aeruginosa, for determining antibacterial properties. Checkerboard assays were also conducted with a panel of antibiotics to determine the synergistic relationship with these hybrids. The results strengthen our hypothesis of linking tobramycin and deferiprone to achieve tetracycline potentiation because the single drug entities (control compounds) are not able to achieve comparable results like our hybrid molecules. Probable mechanism of action could be the internalization effect that renders an increased tetracycline accumulation, allowing it to illicit antimicrobial action with minimal concentration.