The design, synthesis, and microbiological investigation of tobramycin catecholate conjugates
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With the ever-growing threat of multi-drug resistant (MDR) bacteria to the public health, there is a mounting need for the development of novel therapeutics to combat them. Sideromycins are an emerging approach to develop new therapeutics by covalently linking siderophore ligands to antibiotics. This allows these sideromycins to exploit the siderophore uptake mechanism that are fundamental to bacteria, allowing the antibiotic to transverse the bacterial membrane and bypass resistant factors, analogous to a Trojan Horse. Aminoglycosides are a class of broad-spectrum antibiotics that inhibit protein synthesis and are usually reserved for severe bacterial infections, especially those that are caused by Gram-negative bacteria. A common form of resistance against aminoglycoside that develop in clinically isolated Gram-negative bacteria, especially in Pseudomonas aeruginosa strains, is outer membrane impermeability to aminoglycosides. In theory, conjugation of aminoglycosides with a siderophore moiety will allow the aminoglycoside increased access to their intercellular target by exploiting the siderophore uptake system and bypassing impermeability resistance factors. In this study, a new series of aminoglycoside-siderophore conjugates are synthesized by conjugating the aminoglycoside tobramycin to 3,4-dihydroxybenzoic acid, a siderophore ligand, resulting in tobramycin-catecholate (TOB-CAT) conjugates. To elucidate the significance of the catecholate to the activity of the TOB-CAT conjugates, methoxy protected tobramycin-catecholate (TOB-mCAT) conjugates were also synthesized, where the added methoxy groups block the binding capabilities of the catecholate component. In vitro antibacterial studies in MHB show that these TOB-CAT conjugates have P. aeruginosa specific activity, reaching tobramycin susceptibility breakpoints in three P. aeruginosa clinically isolated strains. These studies also showed that the TOB-mCAT conjugates have no activity against the tested Gram-negative strains, indicating the catecholate for the activity observed by the TOB-CAT conjugates. In vitro antibacterial studies in iron deficient cation-adjusted MHB (ID-CAMHB) show a total loss of significant activity of the TOB-CAT conjugates against P. aeruginosa clinical isolates. In vitro combination studies indicate that both the TOB-CAT and TOB-mCAT conjugates are capable of synergizing legacy antibiotics, particularly novobiocin and rifampicin, against Gram-negative bacterial strains in MHB.