The emerging and sustained resistance to currently available antibiotics, and poor prospects for new antibacterial agents, prompt an urgent need for the development of new strategies that can address the problem of growing antibacterial resistance. One such strategy is the development of dual-action hybrid antibiotics: two antibiotics that inhibit dissimilar targets in a bacterial cell are covalently linked into one molecule. The possible benefits include: i) activity against drug-resistant bacteria, ii) an expanded spectrum of activity, and iii) reduced potential for generating new resistance.
Towards these ends, we have designed and synthesized a library of kanamycin A-ciprofloxacin hybrids, connected via 1,2,3-triazole linkers. Their antibiotic activity was tested against various gram-positive and gram-negative bacteria, including resistant strains. We demonstrated that the hybrids exhibit significant antibacterial activity including the bacterial strains resistant to aminoglycosides. Furthermore, they showed significant delay in the development of resistance in both Gram-negative and Gram-positive bacteria, in comparison to that of each parent antibiotic separately or their 1:1 mixture. We conclude that the developed hybrids have great potential as a tool to fight bacterial resistance.
