Covalently Linked Kanamycin – Ciprofloxacin Hybrid Antibiotics as a Tool to Fight Bacterial Resistance

In an attempt to slow down the evolution of resistance of pathogenic bacteria to an action of antibiotics, one approach that has been used with some clinical success is combination therapy; a combination of two or more different antibiotics employing distinct mechanisms of action. However, this strategy cannot address the problem of multiple drug resistance, strains exhibiting resistance to both drugs in combination, and thus requires employment of other families of drugs. In order to prevent some of the limitations of combination therapy, another intriguing approach named ‘‘hybrid antibiotics” has been developed. The strategy is to chemically connect two drugs that target bacterial cells through different modes of action into a single. The covalent connection of two drugs can make the pharmacokinetic properties of the hybrid molecule more predictable, can improve its toxicity profile and can lead to increased retention.

To address the growing problem of antibiotic resistance, a set of 12 hybrid compounds that covalently link fluoroquinolone (ciprofloxacin) and aminoglycoside (kanamycin A) antibiotics (1-12) were synthesized, and their activity was determined against both Gram-negative and Gram-positive bacteria, including resistant strains. The hybrids were antagonistic relative to the ciprofloxacin, but were substantially more potent than the parent kanamycin against Gram-negative bacteria, and overcame most dominant resistance mechanisms to aminoglycosides. Selected hybrids were 42–640 fold poorer inhibitors of bacterial protein synthesis than the parent kanamycin, while they displayed similar inhibitory activity to that of ciprofloxacin against DNA gyrase and topoisomerase IV enzymes. The hybrids showed significant delay of resistance development in both E. coli and B. subtilis in comparison to that of component drugs alone or their 1:1 mixture. More generally, the data suggest that an antagonistic combination of aminoglycoside-fluoroquinolone hybrids can lead to new compounds that slowdown/prevent the emergence of resistance.