Grant: Proof of Principle Program - Phase I

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 amphiphilic aminoglycoside antibiotics restore in vitro activity against clinically relevant and multidrug-resistant bacteria including aminoglycoside-resistant strains of bacteria. 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 types of amphiphilic aminoglycoside antimicrobials. 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. 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.