Grant: CIHR/Regional Partnership Program/Operating Grants

Aminoglycoside antibiotics have been used clinically for decades as potent antimicrobial agents to fight bacterial infections. Although aminoglycosides exhibit potent bactericidal activity, their widespread use has been compromised by toxicity and resistance. The rapid emergence of aminoglycoside antibiotics-resistant strains has instigated research efforts to develop modified semisynthetic aminoglycoside analogs that can delay or avoid acquired resistance by pathogenic bacteria. Previous work in our laboratory has shown that conjugation of the aminoglycoside antibiotics neomycin B and kanamycin A to small molecule-based carriers restores in vitro activity against clinically relevant and multidrug-resistant bacteria including neomycin B-resistant MRSA and Pseudomonas aeruginosa as well as kanamycin A-resistant MRSA, MRSE, and Pseudomonas aeruginosa. In vitro toxicity assays show that most of these analogs have little to no cytotoxicity at their minimal inhibitory concentrations. In this proposal we plan to extend our preliminary work to other more clinically relevant aminoglycosides and carrier molecules. Structure activity relationships and toxicological evaluation will reveal crucial information for lead optimization. The most active and least toxic compounds will undergo in vivo efficacy and in vivo toxicity testing in mouse protection models. Another set of experiments will explore the potential modes of action and resistance development. The data obtained in this study will likely lead to the discovery of novel antibacterial drug leads with low toxicity and novel or combined modes of action and delayed resistance development. Moreover, the data obtained of this study may be applicable to other related polycationic antibiotics.